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1
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Bone RA, Lowndes MP, Raineri S, R Riveiro A, Lundregan SL, Dall M, Sulek K, Romero JAH, Malzard L, Koigi S, Heckenbach IJ, Solis-Mezarino V, Völker-Albert M, Vasilopoulou CG, Meier F, Trusina A, Mann M, L Nielsen M, Treebak JT, Brickman JM. Altering metabolism programs cell identity via NAD +-dependent deacetylation. EMBO J 2025:10.1038/s44318-025-00417-0. [PMID: 40281356 DOI: 10.1038/s44318-025-00417-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/03/2025] [Accepted: 03/03/2025] [Indexed: 04/29/2025] Open
Abstract
Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
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Affiliation(s)
- Robert A Bone
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Molly P Lowndes
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Silvia Raineri
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alba R Riveiro
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sarah L Lundregan
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten Dall
- Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | - Karolina Sulek
- Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | - Jose A H Romero
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Luna Malzard
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
| | - Sandra Koigi
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | - Catherine G Vasilopoulou
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Florian Meier
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Ala Trusina
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Michael L Nielsen
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jonas T Treebak
- Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | - Joshua M Brickman
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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2
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Gonzalez-Jabalera P, Jäschke A. Flavin adenine dinucleotide (FAD) as a non-canonical RNA cap: Mechanisms, functions, and emerging insights. Arch Biochem Biophys 2025; 766:110326. [PMID: 39921141 DOI: 10.1016/j.abb.2025.110326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
Flavin adenine dinucleotide (FAD), a versatile metabolic cofactor, is emerging as an important non-canonical RNA cap across various life domains. This review explores FAD's dual role as a coenzyme and an RNA modifier, focusing on its incorporation as a 5' cap structure during transcription initiation and its subsequent implications for RNA metabolism and cellular functions. A comprehensive view of the mechanisms underlying FAD capping and decapping is presented, highlighting key enzymes that play a role in these processes. FAD-capped RNA is shown to play critical roles in viral replication, as demonstrated in the Hepatitis C virus, where FAD capping supports cellular immune evasion. Analytical techniques, including mass spectrometry and innovative sequencing methodologies, have advanced our understanding of the flavin cap, enabling its identification and quantification in different biological systems. This review underscores the significance of FAD-RNA capping as a novel regulatory mechanism, proposes innovative methodologies for its study, and emphasizes its potential therapeutic applications in viral and cellular biology.
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Affiliation(s)
- Pablo Gonzalez-Jabalera
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
| | - Andres Jäschke
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
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3
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Cano-Besquet S, Park M, Berkley N, Wong M, Ashiqueali S, Noureddine S, Gesing A, Schneider A, Mason J, Masternak MM, Dhahbi JM. Gene and transcript expression patterns, coupled with isoform switching and long non-coding RNA dynamics in adipose tissue, underlie the longevity of Ames dwarf mice. GeroScience 2025; 47:1923-1943. [PMID: 39405012 PMCID: PMC11978586 DOI: 10.1007/s11357-024-01383-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/06/2024] [Indexed: 04/09/2025] Open
Abstract
Our study investigates gene expression in adipose tissue of Ames dwarf (df/df) mice, whose deficiency in growth hormone is linked to health and extended lifespan. Recognizing adipose tissue influence on metabolism, aging, and related diseases, we aim to understand its contribution to the health and longevity of df/df mice. We have identified gene and transcript expression patterns associated with critical biological functions, including metabolism, stress response, and resistance to cancer. Intriguingly, we identified genes that, despite maintaining unchanged expression levels, switch between different isoforms, impacting essential cellular functions such as tumor suppression, oncogenic activity, ATP transport, and lipid biosynthesis and storage. The isoform switching is associated with changes in protein domains, retention of introns, initiation of nonsense-mediated decay, and emergence of intrinsically disordered regions. Moreover, we detected various alternative splicing events that may drive these structural alterations. We also found changes in the expression of long non-coding RNAs (lncRNAs) that may be involved in the aging process and disease resistance by regulating crucial genes in survival and metabolism. Through weighted gene co-expression network analysis, we have linked four lncRNAs with 29 genes, which contribute to protein complexes such as the Mili-Tdrd1-Tdrd12 complex. Beyond safeguarding DNA integrity, this complex also has a wider impact on gene regulation, chromatin structure, and metabolic control. Our detailed investigation provides insight into the molecular foundations of the remarkable health and longevity of df/df mice, emphasizing the significance of adipose tissue in aging and identifying new avenues for health-promoting therapeutic strategies.
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Affiliation(s)
- Sebastian Cano-Besquet
- Department of Medical Education, School of Medicine, California University of Science & Medicine, Colton, CA, USA
| | - Maiyon Park
- Department of Medical Education, School of Medicine, California University of Science & Medicine, Colton, CA, USA
| | | | - Michelle Wong
- Department of Medical Education, School of Medicine, California University of Science & Medicine, Colton, CA, USA
| | - Sarah Ashiqueali
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
| | - Sarah Noureddine
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
| | - Adam Gesing
- Department of Endocrinology of Ageing, Medical University of Lodz, Lodz, Poland
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Jeffrey Mason
- College of Veterinary Medicine, Department of Veterinary Clinical and Life Sciences, Center for Integrated BioSystems, Utah State University, Logan, UT, USA
| | - Michal M Masternak
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland
| | - Joseph M Dhahbi
- Department of Medical Education, School of Medicine, California University of Science & Medicine, Colton, CA, USA.
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4
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Vancamp P, Frapin M, Parnet P, Amarger V. Unraveling the Molecular Mechanisms of the Neurodevelopmental Consequences of Fetal Protein Deficiency: Insights From Rodent Models and Public Health Implications. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100339. [PMID: 39040432 PMCID: PMC11262180 DOI: 10.1016/j.bpsgos.2024.100339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 05/03/2024] [Accepted: 05/19/2024] [Indexed: 07/24/2024] Open
Abstract
Fetal brain development requires increased maternal protein intake to ensure that offspring reach their optimal cognitive potential in infancy and adulthood. While protein deficiency remains a prevalent issue in developing countries, it is also reemerging in Western societies due to the growing adoption of plant-based diets, some of which are monotonous and may fail to provide sufficient amino acids crucial for the brain's critical developmental phase. Confounding variables in human nutritional research have impeded our understanding of the precise impact of protein deficiency on fetal neurodevelopment, as well as its implications for childhood neurocognitive performance. Moreover, it remains unclear whether such deficiency could predispose to mental health problems in adulthood, mirroring observations in individuals exposed to prenatal famine. In this review, we sought to evaluate mechanistic data derived from rodent models, placing special emphasis on the involvement of neuroendocrine axes, the influence of sex and timing, epigenetic modifications, and cellular metabolism. Despite notable progress, critical knowledge gaps remain, including understanding the long-term reversibility of effects due to fetal protein restriction and the interplay between genetic predisposition and environmental factors. Enhancing our understanding of the precise mechanisms that connect prenatal nutrition to brain development in future research endeavors can be significantly advanced by integrating multiomics approaches and utilizing additional alternative models such as nonhuman primates. Furthermore, it is crucial to investigate potential interventions aimed at alleviating adverse outcomes. Ultimately, this research has profound implications for guiding public health strategies aimed at raising awareness about the crucial role of optimal maternal nutrition in supporting fetal neurodevelopment.
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Affiliation(s)
- Pieter Vancamp
- Nantes Université, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, UMR1280, Physiopathologie des Adaptations Nutritionnelles, l'Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Morgane Frapin
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Patricia Parnet
- Nantes Université, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, UMR1280, Physiopathologie des Adaptations Nutritionnelles, l'Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Valérie Amarger
- Nantes Université, Institut National de Recherche pour l'Agriculture, l'alimentation et l'Environnement, UMR1280, Physiopathologie des Adaptations Nutritionnelles, l'Institut des Maladies de l'Appareil Digestif, Nantes, France
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5
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Mondal AK, Gaur M, Advani J, Swaroop A. Epigenome-metabolism nexus in the retina: implications for aging and disease. Trends Genet 2024; 40:718-729. [PMID: 38782642 PMCID: PMC11303112 DOI: 10.1016/j.tig.2024.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 05/25/2024]
Abstract
Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome-metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function.
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Affiliation(s)
- Anupam K Mondal
- Neurobiology, Neurodegeneration, and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mohita Gaur
- Neurobiology, Neurodegeneration, and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jayshree Advani
- Neurobiology, Neurodegeneration, and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Anand Swaroop
- Neurobiology, Neurodegeneration, and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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6
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van der Weijden VA, Stötzel M, Iyer DP, Fauler B, Gralinska E, Shahraz M, Meierhofer D, Vingron M, Rulands S, Alexandrov T, Mielke T, Bulut-Karslioglu A. FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy. Nat Cell Biol 2024; 26:181-193. [PMID: 38177284 PMCID: PMC10866708 DOI: 10.1038/s41556-023-01325-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/29/2023] [Indexed: 01/06/2024]
Abstract
Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is not known. Here we show that mouse embryos in diapause are sustained by using lipids as primary energy source. In vitro, supplementation of embryos with the metabolite L-carnitine balances lipid consumption, puts the embryos in deeper dormancy and boosts embryo longevity. We identify FOXO1 as an essential regulator of the energy balance in dormant embryos and propose, through meta-analyses of dormant cell signatures, that it may be a common regulator of dormancy across adult tissues. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.
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Affiliation(s)
- Vera A van der Weijden
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Maximilian Stötzel
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Dhanur P Iyer
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Beatrix Fauler
- Microscopy and Cryo-Electron Microscopy Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Elzbieta Gralinska
- Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Mohammed Shahraz
- Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany
| | - David Meierhofer
- Mass Spectrometry Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Martin Vingron
- Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Steffen Rulands
- Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
- Arnold Sommerfeld Center for Theoretical Physics, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Theodore Alexandrov
- Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Thorsten Mielke
- Microscopy and Cryo-Electron Microscopy Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Aydan Bulut-Karslioglu
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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7
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Elgazzaz M, Berdasco C, Garai J, Baddoo M, Lu S, Daoud H, Zabaleta J, Mauvais-Jarvis F, Lazartigues E. Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring. Mol Metab 2024; 80:101864. [PMID: 38159883 PMCID: PMC10806294 DOI: 10.1016/j.molmet.2023.101864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/04/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2024] Open
Abstract
OBJECTIVE Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. METHODS C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses. RESULTS Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFβ2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFβ2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFβ receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss. CONCLUSIONS Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way.
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Affiliation(s)
- Mona Elgazzaz
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Clara Berdasco
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
| | - Jone Garai
- Department of Interdisciplinary Oncology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Melody Baddoo
- Department of Pathology and Laboratory Medicine/Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Shiping Lu
- Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hisham Daoud
- School of Computer and Cyber Sciences, Augusta University, Augusta, GA 30901, USA
| | - Jovanny Zabaleta
- Department of Interdisciplinary Oncology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Franck Mauvais-Jarvis
- Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Department of Medicine, Section of Endocrinology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Eric Lazartigues
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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8
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Liu SJ, Casey-Clyde T, Cho NW, Swinderman J, Pekmezci M, Dougherty MC, Foster K, Chen WC, Villanueva-Meyer JE, Swaney DL, Vasudevan HN, Choudhury A, Pak J, Breshears JD, Lang UE, Eaton CD, Hiam-Galvez KJ, Stevenson E, Chen KH, Lien BV, Wu D, Braunstein SE, Sneed PK, Magill ST, Lim D, McDermott MW, Berger MS, Perry A, Krogan NJ, Hansen MR, Spitzer MH, Gilbert L, Theodosopoulos PV, Raleigh DR. Epigenetic reprogramming shapes the cellular landscape of schwannoma. Nat Commun 2024; 15:476. [PMID: 38216587 PMCID: PMC10786948 DOI: 10.1038/s41467-023-40408-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/25/2023] [Indexed: 01/14/2024] Open
Abstract
Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.
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Affiliation(s)
- S John Liu
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
- Arc Institute, Palo Alto, CA, 94304, USA
| | - Tim Casey-Clyde
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Nam Woo Cho
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, and Departments of Otolaryngology, and Microbiology and Immunology, University of California San Francisco, San Francisco, CA, 94115, USA
| | - Jason Swinderman
- Arc Institute, Palo Alto, CA, 94304, USA
- Department of Urology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Melike Pekmezci
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Mark C Dougherty
- Departments of Otolaryngology and Neurosurgery, University of Iowa, Iowa City, IA, 52242, USA
| | - Kyla Foster
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - William C Chen
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Javier E Villanueva-Meyer
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Danielle L Swaney
- J. David Gladstone Institutes, California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Harish N Vasudevan
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Abrar Choudhury
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Joanna Pak
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
- Arc Institute, Palo Alto, CA, 94304, USA
| | - Jonathan D Breshears
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Ursula E Lang
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Dermatology, University of California San Francisco, San Francisco, CA, 94115, USA
| | - Charlotte D Eaton
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kamir J Hiam-Galvez
- Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, and Departments of Otolaryngology, and Microbiology and Immunology, University of California San Francisco, San Francisco, CA, 94115, USA
| | - Erica Stevenson
- J. David Gladstone Institutes, California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Kuei-Ho Chen
- J. David Gladstone Institutes, California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Brian V Lien
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - David Wu
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Steve E Braunstein
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Penny K Sneed
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Stephen T Magill
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Daniel Lim
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | | | - Mitchel S Berger
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Arie Perry
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Nevan J Krogan
- J. David Gladstone Institutes, California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Marlan R Hansen
- Departments of Otolaryngology and Neurosurgery, University of Iowa, Iowa City, IA, 52242, USA
| | - Matthew H Spitzer
- Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, and Departments of Otolaryngology, and Microbiology and Immunology, University of California San Francisco, San Francisco, CA, 94115, USA
| | - Luke Gilbert
- Arc Institute, Palo Alto, CA, 94304, USA
- Department of Urology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Philip V Theodosopoulos
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - David R Raleigh
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.
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9
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Kang J, Benjamin DI, Kim S, Salvi JS, Dhaliwal G, Lam R, Goshayeshi A, Brett JO, Liu L, Rando TA. Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing. Nat Metab 2024; 6:153-168. [PMID: 38243132 PMCID: PMC10976122 DOI: 10.1038/s42255-023-00955-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 11/30/2023] [Indexed: 01/21/2024]
Abstract
The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di/tri-methylation and HP1, decrease with age in muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor S-adenosylmethionine (SAM). We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features, including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation, but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase restores intracellular SAM content and heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity in male and female mice. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during murine MuSC ageing.
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Affiliation(s)
- Jengmin Kang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Daniel I Benjamin
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Soochi Kim
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Jayesh S Salvi
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Gurkamal Dhaliwal
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Richard Lam
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Armon Goshayeshi
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Jamie O Brett
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
| | - Ling Liu
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
- Department of Neurology and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Thomas A Rando
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Neurology Service, Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA.
- Department of Neurology and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
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10
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Furlan A, Petrus P. Brain-body communication in metabolic control. Trends Endocrinol Metab 2023; 34:813-822. [PMID: 37716877 DOI: 10.1016/j.tem.2023.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 09/18/2023]
Abstract
A thorough understanding of the mechanisms controlling energy homeostasis is needed to prevent and treat metabolic morbidities. While the contribution of organs such as the liver, muscle, adipose tissue, and pancreas to the regulation of energy has received wide attention, less is known about the interplay with the nervous system. Here, we highlight the role of the nervous systems in regulating metabolism beyond the classic hypothalamic endocrine signaling models and discuss the contribution of circadian rhythms, higher brain regions, and sociodemographic variables in the energy equation. We infer that interdisciplinary approaches are key to conceptually advancing the current research frontier and devising innovative therapies to prevent and treat metabolic disease.
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Affiliation(s)
- Alessandro Furlan
- Department of Neuroscience, Karolinska Institutet, Stockholm 171 65, Sweden.
| | - Paul Petrus
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141 86, Sweden.
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11
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Sandalova E, Goh J, Lim ZX, Lim ZM, Barardo D, Dorajoo R, Kennedy BK, Maier AB. Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)-intervention study protocol. GeroScience 2023; 45:2897-2907. [PMID: 37217632 PMCID: PMC10643463 DOI: 10.1007/s11357-023-00813-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/28/2023] [Indexed: 05/24/2023] Open
Abstract
Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the potential to increase healthspan and lifespan. Even though many of them have been tested in animal models, the translation to humans is limited. Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans. ABLE is a double blinded placebo-controlled randomized trial (RCT) of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow up including 120 40-60-year-old healthy individuals with a higher DNA methylation age compared to their chronological age. The primary outcome is the decrease in DNA methylation age from baseline to the end of the intervention. A total of 120 participants will be randomized to receive either sustained release Ca-AKG or placebo. Secondary outcomes include changes in the inflammatory and metabolic parameters in blood, handgrip strength and leg extension strength, arterial stiffness, skin autofluorescence, and aerobic capacity from baseline to 3 months, 6 months, and 9 months. This study will recruit middle-aged participants with an older DNA methylation age compared to their chronological age, and test whether supplementation with Ca-AKG can reduce DNA methylation age. This study is unique in its inclusion of biologically older participants.
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Affiliation(s)
- Elena Sandalova
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore.
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore.
| | - Jorming Goh
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Zi Xiang Lim
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Zhi Meng Lim
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Diogo Barardo
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
| | - Brian K Kennedy
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Andrea B Maier
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117456, Singapore.
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore.
- Department of Human Movement Sciences, @AgeAmsterdam, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, Netherlands.
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12
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Bennett S, Sato S. Metabolic elasticity: A new measure of age. Cell Metab 2023; 35:1495-1497. [PMID: 37673034 DOI: 10.1016/j.cmet.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Promoting healthy aging is contingent on understanding the underlying mechanisms for the age-associated decline in metabolic physiology. Through developing a novel concept of "metabolic elasticity" to evaluate metabolic adaptability in response to cyclical changes in energy balance, Zhou et al. present an impactful gauge of metabolic health that is particularly relevant to aging.
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Affiliation(s)
- Samuel Bennett
- Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, TX, USA
| | - Shogo Sato
- Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, TX, USA.
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13
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Khan SU, Rayees S, Sharma P, Malik F. Targeting redox regulation and autophagy systems in cancer stem cells. Clin Exp Med 2023; 23:1405-1423. [PMID: 36473988 DOI: 10.1007/s10238-022-00955-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 11/16/2022] [Indexed: 12/12/2022]
Abstract
Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).
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Affiliation(s)
- Sameer Ullah Khan
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sheikh Rayees
- PK PD Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Pankaj Sharma
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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14
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Bar-Sadeh B, Pnueli L, Keestra S, Bentley GR, Melamed P. Srd5a1 is Differentially Regulated and Methylated During Prepubertal Development in the Ovary and Hypothalamus. J Endocr Soc 2023; 7:bvad108. [PMID: 37646011 PMCID: PMC10461783 DOI: 10.1210/jendso/bvad108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Indexed: 09/01/2023] Open
Abstract
5α-reductase-1 catalyzes production of various steroids, including neurosteroids. We reported previously that expression of its encoding gene, Srd5a1, drops in murine ovaries and hypothalamic preoptic area (POA) after early-life immune stress, seemingly contributing to delayed puberty and ovarian follicle depletion, and in the ovaries the first intron was more methylated at two CpGs. Here, we hypothesized that this CpG-containing locus comprises a methylation-sensitive transcriptional enhancer for Srd5a1. We found that ovarian Srd5a1 mRNA increased 8-fold and methylation of the same two CpGs decreased up to 75% between postnatal days 10 and 30. Estradiol (E2) levels rise during this prepubertal stage, and exposure of ovarian cells to E2 increased Srd5a1 expression. Chromatin immunoprecipitation in an ovarian cell line confirmed ESR1 binding to this differentially methylated genomic region and enrichment of the enhancer modification, H3K4me1. Targeting dCas9-DNMT3 to this locus increased CpG2 methylation 2.5-fold and abolished the Srd5a1 response to E2. In the POA, Srd5a1 mRNA levels decreased 70% between postnatal days 7 and 10 and then remained constant without correlation to CpG methylation levels. Srd5a1 mRNA levels did not respond to E2 in hypothalamic GT1-7 cells, even after dCas9-TET1 reduced CpG1 methylation by 50%. The neonatal drop in POA Srd5a1 expression occurs at a time of increasing glucocorticoids, and treatment of GT1-7 cells with dexamethasone reduced Srd5a1 mRNA levels; chromatin immunoprecipitation confirmed glucocorticoid receptor binding at the enhancer. Our findings on the tissue-specific regulation of Srd5a1 and its methylation-sensitive control by E2 in the ovaries illuminate epigenetic mechanisms underlying reproductive phenotypic variation that impact life-long health.
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Affiliation(s)
- Ben Bar-Sadeh
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Lilach Pnueli
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Sarai Keestra
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
- Department of Anthropology, Durham University, Durham, DH1 3LE, UK
| | | | - Philippa Melamed
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
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15
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Sato S, Hishida T, Kinouchi K, Hatanaka F, Li Y, Nguyen Q, Chen Y, Wang PH, Kessenbrock K, Li W, Izpisua Belmonte JC, Sassone-Corsi P. The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming. Cell Rep 2023; 42:112590. [PMID: 37261952 DOI: 10.1016/j.celrep.2023.112590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/28/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023] Open
Abstract
Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.
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Affiliation(s)
- Shogo Sato
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA; Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, TX, USA.
| | - Tomoaki Hishida
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan
| | - Kenichiro Kinouchi
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Fumiaki Hatanaka
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA
| | - Yumei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Quy Nguyen
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Yumay Chen
- UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Ping H Wang
- UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Kai Kessenbrock
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Juan Carlos Izpisua Belmonte
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA.
| | - Paolo Sassone-Corsi
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
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16
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Kravitz CJ, Yan Q, Nguyen DX. Epigenetic markers and therapeutic targets for metastasis. Cancer Metastasis Rev 2023; 42:427-443. [PMID: 37286865 PMCID: PMC10595046 DOI: 10.1007/s10555-023-10109-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 05/19/2023] [Indexed: 06/09/2023]
Abstract
The last few years have seen an increasing number of discoveries which collectively demonstrate that histone and DNA modifying enzyme modulate different stages of metastasis. Moreover, epigenomic alterations can now be measured at multiple scales of analysis and are detectable in human tumors or liquid biopsies. Malignant cell clones with a proclivity for relapse in certain organs may arise in the primary tumor as a consequence of epigenomic alterations which cause a loss in lineage integrity. These alterations may occur due to genetic aberrations acquired during tumor progression or concomitant to therapeutic response. Moreover, evolution of the stroma can also alter the epigenome of cancer cells. In this review, we highlight current knowledge with a particular emphasis on leveraging chromatin and DNA modifying mechanisms as biomarkers of disseminated disease and as therapeutic targets to treat metastatic cancers.
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Affiliation(s)
- Carolyn J Kravitz
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Qin Yan
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA.
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06520, USA.
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, 06520, USA.
- Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, 06520, USA.
| | - Don X Nguyen
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA.
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06520, USA.
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, 06520, USA.
- Department of Internal Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, CT, 06520, USA.
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17
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Garige M, Poncet S, Norris A, Chou CK, Wu WW, Shen RF, Greenberg JW, Krane LS, Sourbier C. Extended Opioid Exposure Modulates the Molecular Metabolism of Clear Cell Renal Cell Carcinoma. Life (Basel) 2023; 13:life13051196. [PMID: 37240841 DOI: 10.3390/life13051196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/06/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Opioids are commonly prescribed for extended periods of time to patients with advanced clear cell renal cell carcinoma to assist with pain management. Because extended opioid exposure has been shown to affect the vasculature and to be immunosuppressive, we investigated how it may affect the metabolism and physiology of clear cell renal cell carcinoma. RNA sequencing of a limited number of archived patients' specimens with extended opioid exposure or non-opioid exposure was performed. Immune infiltration and changes in the microenvironment were evaluated using CIBERSORT. A significant decrease in M1 macrophages and T cells CD4 memory resting immune subsets was observed in opioid-exposed tumors, whereas the changes observed in other immune cells were not statistically significant. Further RNA sequencing data analysis showed that differential expression of KEGG signaling pathways was significant between non-opioid-exposed specimens and opioid-exposed specimens, with a shift from a gene signature consistent with aerobic glycolysis to a gene signature consistent with the TCA cycle, nicotinate metabolism, and the cAMP signaling pathway. Together, these data suggest that extended opioid exposure changes the cellular metabolism and immune homeostasis of ccRCC, which might impact the response to therapy of these patients, especially if the therapy is targeting the microenvironment or metabolism of ccRCC tumors.
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Affiliation(s)
- Mamatha Garige
- Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Sarah Poncet
- Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Alexis Norris
- Division of Animal Bioengineering and Cellular Therapies, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20852, USA
| | - Chao-Kai Chou
- Facility for Biotechnology Resources, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Wells W Wu
- Facility for Biotechnology Resources, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Rong-Fong Shen
- Facility for Biotechnology Resources, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Jacob W Greenberg
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Louis Spencer Krane
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Carole Sourbier
- Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
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18
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Liu Z, Liang Q, Ren Y, Guo C, Ge X, Wang L, Cheng Q, Luo P, Zhang Y, Han X. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther 2023; 8:200. [PMID: 37179335 PMCID: PMC10182360 DOI: 10.1038/s41392-023-01451-2] [Citation(s) in RCA: 282] [Impact Index Per Article: 141.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 03/24/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells, and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging. Although the underlying molecular mechanisms remain to be addressed, it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence. Potential counteractive measures will be discussed, including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence. In recent years, immunosenescence has attracted increasing attention for its role in tumor development. As a result of the limited participation of elderly patients, the impact of immunosenescence on cancer immunotherapy is unclear. Despite some surprising results from clinical trials and drugs, it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
- Interventional Institute of Zhengzhou University, 450052, Zhengzhou, Henan, China
- Interventional Treatment and Clinical Research Center of Henan Province, 450052, Zhengzhou, Henan, China
| | - Qimeng Liang
- Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 4500052, Henan, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
| | - Chunguang Guo
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
| | - Xiaoyong Ge
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
| | - Libo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China.
- Interventional Institute of Zhengzhou University, 450052, Zhengzhou, Henan, China.
- Interventional Treatment and Clinical Research Center of Henan Province, 450052, Zhengzhou, Henan, China.
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19
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Vogt MC, Hobert O. Starvation-induced changes in somatic insulin/IGF-1R signaling drive metabolic programming across generations. SCIENCE ADVANCES 2023; 9:eade1817. [PMID: 37027477 PMCID: PMC10081852 DOI: 10.1126/sciadv.ade1817] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 03/08/2023] [Indexed: 05/30/2023]
Abstract
Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating, and manifesting changes to metabolism and behavior across generations remain scarce. By using a starvation paradigm in Caenorhabditis elegans, we show that starvation-induced changes in dauer formation-16/forkhead box transcription factor class O (DAF-16/FoxO) activity, the main downstream target of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations.
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20
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Smith N, Shirazi S, Cakouros D, Gronthos S. Impact of Environmental and Epigenetic Changes on Mesenchymal Stem Cells during Aging. Int J Mol Sci 2023; 24:ijms24076499. [PMID: 37047469 PMCID: PMC10095074 DOI: 10.3390/ijms24076499] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 03/31/2023] Open
Abstract
Many crucial epigenetic changes occur during early skeletal development and throughout life due to aging, disease and are heavily influenced by an individual’s lifestyle. Epigenetics is the study of heritable changes in gene expression as the result of changes in the environment without any mutation in the underlying DNA sequence. The epigenetic profiles of cells are dynamic and mediated by different mechanisms, including histone modifications, non-coding RNA-associated gene silencing and DNA methylation. Given the underlining role of dysfunctional mesenchymal tissues in common age-related skeletal diseases such as osteoporosis and osteoarthritis, investigations into skeletal stem cells or mesenchymal stem cells (MSC) and their functional deregulation during aging has been of great interest and how this is mediated by an evolving epigenetic landscape. The present review describes the recent findings in epigenetic changes of MSCs that effect growth and cell fate determination in the context of aging, diet, exercise and bone-related diseases.
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Affiliation(s)
- Nicholas Smith
- Mesenchymal Stem Cell Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
| | - Suzanna Shirazi
- Mesenchymal Stem Cell Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
| | - Dimitrios Cakouros
- Mesenchymal Stem Cell Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
- Correspondence: (D.C.); (S.G.); Tel.: +61-8-8128-4395 (S.G.)
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
- Correspondence: (D.C.); (S.G.); Tel.: +61-8-8128-4395 (S.G.)
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21
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Day time-restricted feeding shows differential synchronizing effects on age-related changes of serotonin metabolism in SCN and the pineal gland in male Wistar rats. Biogerontology 2022; 23:771-788. [PMID: 36322233 DOI: 10.1007/s10522-022-09994-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 10/07/2022] [Indexed: 12/12/2022]
Abstract
The circadian timing system is synchronized by the environmental photic and non-photic signals. Light is the major cue that entrains the master circadian oscillator located in suprachiasmatic nucleus (SCN). With aging condition ocular light impairs because of the age-related deficiencies in the eye as a result the clock becomes less sensitive to light. In such case non-photic cues may play a major role in synchronizing the clock. Earlier studies have linked altered meal timings to induce many physiological changes including serotonin in different brain regions such as hypothalamus, brain stem and striatum. Much is not known about the effect of timed food restriction as a non-photic stimulus on serotonergic system in SCN under aging condition. We report here the synchronizing effects of time-restricted feeding (TRF) as a non-photic stimulus on serotonin and its related metabolites in the SCN and pineal gland of male Wistar rats upon aging. Under food restriction daily rhythmicity of serotonin 5-HT and 5-HTOH was abolished whereas NAS, 5-MIAA and NAT showed a significant decrease in their daily pulses upon food restriction in 3 months (m) old rats. Under forced day time feeding schedule the mean 24 h levels of serotonin have significantly decreased in 12 and 24 m old animals in SCN and pineal gland. Most of the serotonin metabolites in the SCN and pineal gland of 12 and 24 m old ad libitum fed group rats have shown rhythmicity. 5-HT, NAS, MEL and NAT have shown daily rhythm in the SCN of 12 and 24 m old rats whereas 5-MIAA and 5-MTOH did not show daily rhythm in both the age groups. The mean 24 h levels of 5-HTP, 5-HIAA, 5-MIAA, 5-MTOH, MEL and NAT were increased in the pineal gland of 12 and 24 months old rats. This work help demonstrate the role of TRF in synchronising age induced desynchronization in serotonin metabolome.
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22
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Wang N, Chen L, Yi K, Zhang B, Li C, Zhou X. The effects of microbiota on reproductive health: A review. Crit Rev Food Sci Nutr 2022; 64:1486-1507. [PMID: 36066460 DOI: 10.1080/10408398.2022.2117784] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Reproductive issues are becoming an increasing global problem. There is increasing interest in the relationship between microbiota and reproductive health. Stable microbiota communities exist in the gut, reproductive tract, uterus, testes, and semen. Various effects (e.g., epigenetic modifications, nervous system, metabolism) of dysbiosis in the microbiota can impair gamete quality; interfere with zygote formation, embryo implantation, and embryo development; and increase disease susceptibility, thus adversely impacting reproductive capacity and pregnancy. The maintenance of a healthy microbiota can protect the host from pathogens, increase reproductive potential, and reduce the rates of adverse pregnancy outcomes. In conclusion, this review discusses microbiota in the male and female reproductive systems of multiple animal species. It explores the effects and mechanisms of microbiota on reproduction, factors that influence microbiota composition, and applications of microbiota in reproductive disorder treatment and detection. The findings support novel approaches for managing reproductive diseases through microbiota improvement and monitoring. In addition, it will stimulate further systematic explorations of microbiota-mediated effects on reproduction.
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Affiliation(s)
- Nan Wang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Lu Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Kangle Yi
- Hunan Institute of Animal and Veterinary Science, Changsha, China
| | - Baizhong Zhang
- Hunan Institute of Animal and Veterinary Science, Changsha, China
| | - Chunjin Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xu Zhou
- College of Animal Sciences, Jilin University, Changchun, China
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23
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Sharma S, Yang J, Doamekpor SK, Grudizen-Nogalska E, Tong L, Kiledjian M. Identification of a novel deFADding activity in human, yeast and bacterial 5' to 3' exoribonucleases. Nucleic Acids Res 2022; 50:8807-8817. [PMID: 35904778 PMCID: PMC9410882 DOI: 10.1093/nar/gkac617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/18/2022] [Accepted: 07/21/2022] [Indexed: 11/19/2022] Open
Abstract
Identification of metabolite caps including FAD on the 5' end of RNA has uncovered a previously unforeseen intersection between cellular metabolism and gene expression. To understand the function of FAD caps in cellular physiology, we characterised the proteins interacting with FAD caps in budding yeast. Here we demonstrate that highly conserved 5'-3' exoribonucleases, Xrn1 and Rat1, physically interact with the RNA 5' FAD cap and both possess FAD cap decapping (deFADding) activity and subsequently degrade the resulting RNA. Xrn1 deFADding activity was also evident in human cells indicating its evolutionary conservation. Furthermore, we report that the recently identified bacterial 5'-3' exoribonuclease RNase AM also possesses deFADding activity that can degrade FAD-capped RNAs in vitro and in Escherichia coli cells. To gain a molecular understanding of the deFADding reaction, an RNase AM crystal structure with three manganese ions coordinated by a sulfate molecule and the active site amino acids was generated that provided details underlying hydrolysis of the FAD cap. Our findings reveal a general propensity for 5'-3' exoribonucleases to hydrolyse and degrade RNAs with 5' end noncanonical caps in addition to their well characterized 5' monophosphate RNA substrates indicating an intrinsic property of 5'-3' exoribonucleases.
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Affiliation(s)
- Sunny Sharma
- Department of Cell Biology and Neurosciences, Rutgers, University, Piscataway, NJ 08854, USA
| | - Jun Yang
- Department of Cell Biology and Neurosciences, Rutgers, University, Piscataway, NJ 08854, USA
| | - Selom K Doamekpor
- Department Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Ewa Grudizen-Nogalska
- Department of Cell Biology and Neurosciences, Rutgers, University, Piscataway, NJ 08854, USA
| | - Liang Tong
- Department Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Megerditch Kiledjian
- Department of Cell Biology and Neurosciences, Rutgers, University, Piscataway, NJ 08854, USA
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24
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Stifel U, Caratti G, Tuckermann J. Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors. FEBS Lett 2022; 596:2617-2629. [PMID: 35997656 DOI: 10.1002/1873-3468.14474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/14/2022] [Accepted: 07/04/2022] [Indexed: 11/07/2022]
Abstract
Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors (PPARs), 1,25-dihydroxyvitamin D(3) receptor (VDR), liver X receptors (LXRs), glucocorticoid receptors (GRs), estrogen-related receptor α (ERRα) and Nur77, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti-inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.
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Affiliation(s)
- Ulrich Stifel
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany
| | - Giorgio Caratti
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany.,NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Jan Tuckermann
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany
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25
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Izquierdo-Torres E, Hernández-Oliveras A, Lozano-Arriaga D, Zarain-Herzberg Á. Obesity, the other pandemic: linking diet and carcinogenesis by epigenetic mechanisms. J Nutr Biochem 2022; 108:109092. [PMID: 35718098 DOI: 10.1016/j.jnutbio.2022.109092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 03/19/2022] [Accepted: 05/30/2022] [Indexed: 11/25/2022]
Abstract
Both obesity and cancer are complex medical conditions that are considered public health problems. The influence of obesity on the predisposition to develop various types of cancer has been observed in a wide variety of studies. Due to their importance as public health problems, and the close relationship between both conditions, it is important to be able to understand and associate them mechanistically. In this review article, we intend to go a little further, by finding relationships between lifestyle, which can lead a person to develop obesity, and how it influences at the cellular and molecular level, affecting gene expression to favor signaling pathways or transcriptional programs involved in cancer. We describe how products of metabolism and intermediate metabolism can affect chromatin structure, participating in the regulation (or dysregulation) of gene expression, and we show an analysis of genes that are responsive to diets high in sugar and fat, and how their epigenetic landscape is altered.
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Affiliation(s)
- Eduardo Izquierdo-Torres
- Departamento de Bioquímica, Facultad de Medicina. Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Andrés Hernández-Oliveras
- Departamento de Bioquímica, Facultad de Medicina. Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Dalia Lozano-Arriaga
- Departamento de Bioquímica, Facultad de Medicina. Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Ángel Zarain-Herzberg
- Departamento de Bioquímica, Facultad de Medicina. Universidad Nacional Autónoma de México, Ciudad de México, México.
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26
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Baklaushev VP, Samoilova EM, Kalsin VA, Yusubalieva GM. Aging and “rejuvenation” of resident stem cells — a new way to active longevity? КЛИНИЧЕСКАЯ ПРАКТИКА 2022; 13:79-91. [DOI: 10.17816/clinpract104999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
This review presents the current data on the methodology for assessing the biological and epigenetic age, describes the concept of the epigenetic clock, and characterizes the main types of resident stem cells and the specifics of their aging. It has been shown that age-related changes in organs and tissues, as well as age-related diseases, are largely due to the aging of resident stem cells. The latter represent an attractive target for cell rejuvenation, as they can be isolated, cultured ex vivo, modified, and re-introduced into the resident niches. Two main methodologies for the cellular rejuvenation are presented: genetic reprogramming with zeroing the age of a cell using transient expression of transcription factors, and various approaches to epigenetic rejuvenation. The close relationship between aging, regeneration, and oncogenesis, and between these factors and the functioning of resident stem cell niches requires further precision studies, which, we are sure, can result in the creation of an effective anti-aging strategy and prolongation of human active life.
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27
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Dollet L, Kuefner M, Caria E, Rizo-Roca D, Pendergrast L, Abdelmoez AM, Karlsson HK, Björnholm M, Dalbram E, Treebak JT, Harada J, Näslund E, Rydén M, Zierath JR, Pillon NJ, Krook A. Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes. Diabetes 2022; 71:624-636. [PMID: 35040927 PMCID: PMC8965677 DOI: 10.2337/db20-0814] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/23/2021] [Indexed: 11/23/2022]
Abstract
Dysregulation of skeletal muscle metabolism influences whole-body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes-associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlates inversely with BMI and insulin resistance index (HOMA-IR) in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulate the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase in glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.
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Affiliation(s)
- Lucile Dollet
- Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Michael Kuefner
- Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Elena Caria
- Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - David Rizo-Roca
- Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Logan Pendergrast
- Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Ahmed M. Abdelmoez
- Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Håkan K.R. Karlsson
- Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Marie Björnholm
- Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Emilie Dalbram
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jonas T. Treebak
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jun Harada
- Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Erik Näslund
- Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Mikael Rydén
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Juleen R. Zierath
- Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Nicolas J. Pillon
- Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Anna Krook
- Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Corresponding author: Anna Krook,
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28
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Zhang W, Li J, Duan Y, Li Y, Sun Y, Sun H, Yu X, Gao X, Zhang C, Zhang H, Shi Y, He X. Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence. Stem Cell Rev Rep 2022; 18:1728-1742. [PMID: 35258787 DOI: 10.1007/s12015-022-10348-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2022] [Indexed: 02/06/2023]
Abstract
Stem cell senescence and exhaustion are closely related to organ failure and individual aging, which not only induces age-related diseases, but also hinders stem cell applications in regenerative medicine. Thus, it's imminent to find effective ways to delay and retrieve stem cell senescence. Metabolic abnormalities are one of the main characteristics of age-associated declines in stem cell function. Understanding the underlying mechanisms may reveal potential strategies for ameliorating age-associated phenotypes and treating age-related diseases. This review focuses on recent advances in the association between metabolism including glucose, lipid, glutamine and NAD+ metabolism and stem cell senescence, as well as the other properties like proliferation and differentiation. Layers of studies are summarized to demonstrate how metabolism varies in senescent stem cells and how metabolic reprogramming regulates stem cell senescence. Additionally, we mentioned some recent progress in therapeutic strategies to rejuvenate dysfunctional aged stem cells. Finally, a brief conclusion about the prospect of metabolic regulation as a potential strategy for rescuing stem cell senescence is displayed. Stem cell senescence is induced by the metabolic reprogramming. The metabolic alterations of glucose, lipid, glutamine and NAD+ can conversely facilitate or inhibit stem cell senescence. Glycolysis, OXPHOS and PPP are all attenuated. But gluconeogenesis alterations still remain unclear. In lipid metabolisms, both FAO and DNL are suppressed. As for the glutamine metabolism, stem cells' dependence on glutamine is enhanced. Last, NAD+ metabolism undergoes a down-regulated synthesis and up-regulated consumption. All these alterations can be potential targets for reversing stem cell senescence.
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Affiliation(s)
- Wenxin Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Jiayu Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Yuchi Duan
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Yanlin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Yanan Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Hui Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Xiao Yu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Xingyu Gao
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Chang Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Haiying Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Yingai Shi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Xu He
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
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29
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Møller SH, Hsueh PC, Yu YR, Zhang L, Ho PC. Metabolic programs tailor T cell immunity in viral infection, cancer, and aging. Cell Metab 2022; 34:378-395. [PMID: 35235773 DOI: 10.1016/j.cmet.2022.02.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 12/13/2021] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
Abstract
Productive T cell responses to infection and cancer rely on coordinated metabolic reprogramming and epigenetic remodeling among the immune cells. In particular, T cell effector and memory differentiation, exhaustion, and senescence/aging are tightly regulated by the metabolism-epigenetics axis. In this review, we summarize recent advances of how metabolic circuits combined with epigenetic changes dictate T cell fate decisions and shape their functional states. We also discuss how the metabolic-epigenetic axis orchestrates T cell exhaustion and explore how physiological factors, such as diet, gut microbiota, and the circadian clock, are integrated in shaping T cell epigenetic modifications and functionality. Furthermore, we summarize key features of the senescent/aged T cells and discuss how to ameliorate vaccination- and COVID-induced T cell dysfunctions by metabolic modulations. An in-depth understanding of the unexplored links between cellular metabolism and epigenetic modifications in various physiological or pathological contexts has the potential to uncover novel therapeutic strategies for fine-tuning T cell immunity.
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Affiliation(s)
- Sofie Hedlund Møller
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Pei-Chun Hsueh
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Yi-Ru Yu
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
| | - Lianjun Zhang
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
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30
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Nunn ER, Shinde AB, Zaganjor E. Weighing in on Adipogenesis. Front Physiol 2022; 13:821278. [PMID: 35283790 PMCID: PMC8914022 DOI: 10.3389/fphys.2022.821278] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/20/2022] [Indexed: 12/13/2022] Open
Abstract
Obesity is a growing health concern worldwide because of its contribution to metabolic syndrome, type II diabetes, insulin resistance (IR), and numerous cancers. In obesity, white adipose tissue (WAT) expands through two mechanisms: increase in adipocyte cell number by precursor cell differentiation through the process of adipogenesis (hyperplasia) and increase in existing mature adipocyte cell size (hypertrophy). While hypertrophy is associated with the negative effects of obesity on metabolic health, such as inflammation and lipotoxicity, adipogenesis prevents obesity-mediated metabolic decline. Moreover, in metabolically healthy obesity adipogenesis is increased. Thus, it is vital to understand the mechanistic basis for adipose expansion to inform novel therapeutic approaches to mitigate the dysfunction of this tissue and associated diseases. In this mini-review, we summarize recent studies on the regulation of adipogenesis and provide a perspective on targeting adipogenesis as a potential therapeutic avenue for metabolic disorders.
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31
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Maqdasy S, Lecoutre S, Renzi G, Frendo-Cumbo S, Rizo-Roca D, Moritz T, Juvany M, Hodek O, Gao H, Couchet M, Witting M, Kerr A, Bergo MO, Choudhury RP, Aouadi M, Zierath JR, Krook A, Mejhert N, Rydén M. Impaired phosphocreatine metabolism in white adipocytes promotes inflammation. Nat Metab 2022; 4:190-202. [PMID: 35165448 PMCID: PMC8885409 DOI: 10.1038/s42255-022-00525-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 01/05/2022] [Indexed: 02/07/2023]
Abstract
The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.
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Grants
- SM was supported by the Université Clermont Auvergne, Société Francophone du Diabète and Fondation Bettencourt Schueller.
- S.F.C. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet.
- the NovoNordisk Foundation (NNF20OC0061149), CIMED, Swedish Research Council.
- Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
- Margareta af Uggla’s foundation, the Swedish Research Council, ERC-SyG SPHERES (856404 to M.R.), the NovoNordisk Foundation (including the Tripartite Immuno-metabolism Consortium Grant Number NNF15CC0018486, the MSAM consortium NNF15SA0018346 and the MeRIAD consortium Grant number 0064142), Knut and Alice Wallenbergs Foundation, CIMED, the Swedish Diabetes Foundation, the Stockholm County Council and the Strategic Research Program in Diabetes at Karolinska Institutet.
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Affiliation(s)
- Salwan Maqdasy
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
- CHU Clermont-Ferrand, Service d'endocrinologie, diabétologie et maladies métaboliques, Clermont-Ferrand, France
- Laboratoire GReD, Université Clermont Auvergne, Faculté de Médecine, Clermont Ferrand, France
| | - Simon Lecoutre
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
| | - Gianluca Renzi
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
| | - Scott Frendo-Cumbo
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
| | - David Rizo-Roca
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Thomas Moritz
- Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden
- The NovoNordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marta Juvany
- Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Ondrej Hodek
- Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Hui Gao
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Morgane Couchet
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
| | - Michael Witting
- Metabolomics and proteomics core (MPC), Helmholtz Zentrum München, Neuherberg, Germany
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany
- Chair of Analytical Food Chemistry, TUM School of Life Sciences, Freising, Germany
| | - Alastair Kerr
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
| | - Martin O Bergo
- Department of Biosciences and Nutrition, Karolinska Comprehensive Cancer Center, Karolinska Institutet, Huddinge, Sweden
| | | | - Myriam Aouadi
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
| | - Juleen R Zierath
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Anna Krook
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Niklas Mejhert
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
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32
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Unconventional metabolites in chromatin regulation. Biosci Rep 2022; 42:230604. [PMID: 34988581 PMCID: PMC8777195 DOI: 10.1042/bsr20211558] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/04/2022] [Accepted: 01/04/2022] [Indexed: 11/17/2022] Open
Abstract
Chromatin, the complex of DNA and histone proteins, serves as a main integrator of cellular signals. Increasing evidence links cellular functional to chromatin state. Indeed, different metabolites are emerging as modulators of chromatin function and structure. Alterations in chromatin state are decisive for regulating all aspects of genome function and ultimately have the potential to produce phenotypic changes. Several metabolites such as acetyl-CoA, S-adenosylmethionine (SAM) or adenosine triphosphate (ATP) have now been well characterized as main substrates or cofactors of chromatin-modifying enzymes. However, there are other metabolites that can directly interact with chromatin influencing its state or that modulate the properties of chromatin regulatory factors. Also, there is a growing list of atypical enzymatic and nonenzymatic chromatin modifications that originate from different cellular pathways that have not been in the limelight of chromatin research. Here, we summarize different properties and functions of uncommon regulatory molecules originating from intermediate metabolism of lipids, carbohydrates and amino acids. Based on the various modes of action on chromatin and the plethora of putative, so far not described chromatin-regulating metabolites, we propose that there are more links between cellular functional state and chromatin regulation to be discovered. We hypothesize that these connections could provide interesting starting points for interfering with cellular epigenetic states at a molecular level.
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33
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Tuning up an aged clock: Circadian clock regulation in metabolism and aging. TRANSLATIONAL MEDICINE OF AGING 2022. [DOI: 10.1016/j.tma.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Zakharova AN, Kironenko TA, Milovanova KG, Orlova AA, Dyakova EY, Kalinnikova Yu G, Kabachkova AV, Chibalin AV, Kapilevich LV. Treadmill Training Effect on the Myokines Content in Skeletal Muscles of Mice With a Metabolic Disorder Model. Front Physiol 2021; 12:709039. [PMID: 34858197 PMCID: PMC8631430 DOI: 10.3389/fphys.2021.709039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 10/12/2021] [Indexed: 02/02/2023] Open
Abstract
The effect of treadmill training loads on the content of cytokines in mice skeletal muscles with metabolic disorders induced by a 16 week high fat diet (HFD) was studied. The study included accounting the age and biorhythmological aspects. In the experiment, mice were used at the age of 4 and 32 weeks, by the end of the experiment—respectively 20 and 48 weeks. HFD feeding lasted 16 weeks. Treadmill training were carried out for last 4 weeks six times a week, the duration 60 min and the speed from 15 to 18 m/min. Three modes of loading were applied. The first subgroup was subjected to stress in the morning hours (light phase); the second subgroup was subjected to stress in the evening hours (dark phase); the third subgroup was subjected to loads in the shift mode (the first- and third-weeks treadmill training was used in the morning hours, the second and fourth treadmill training was used in the evening hours). In 20-week-old animals, the exercise effect does not depend on the training regime, however, in 48-week-old animals, the decrease in body weight in mice with the shift training regime was more profound. HFD affected muscle myokine levels. The content of all myokines, except for LIF, decreased, while the concentration of CLCX1 decreased only in young animals in response to HFD. The treadmill training caused multidirectional changes in the concentration of myokines in muscle tissue. The IL-6 content changed most profoundly. These changes were observed in all groups of animals. The changes depended to the greatest extent on the training time scheme. The effect of physical activity on the content of IL-15 in the skeletal muscle tissue was observed mostly in 48-week-old mice. In 20-week-old animals, physical activity led to an increase in the concentration of LIF in muscle tissue when applied under the training during the dark phase or shift training scheme. In the HFD group, this effect was significantly more pronounced. The content of CXCL1 did not change with the use of treadmill training in almost all groups of animals. Physical activity, introduced considering circadian rhythms, is a promising way of influencing metabolic processes both at the cellular and systemic levels, which is important for the search for new ways of correcting metabolic disorders.
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Affiliation(s)
- Anna Nikolaevna Zakharova
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia
| | | | - Kseniia G Milovanova
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia
| | - A A Orlova
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia
| | - E Yu Dyakova
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia
| | - G Kalinnikova Yu
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia
| | - Anastasia V Kabachkova
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia
| | - Alexander V Chibalin
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia.,Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
| | - Leonid V Kapilevich
- Department of Sport Tourism, Sport Physiology and Medicine, National Research Tomsk State University, Tomsk, Russia.,Central Research Laboratory, Siberian State Medical University, Tomsk, Russia
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35
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Linking Depression to Epigenetics: Role of the Circadian Clock. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1344:43-53. [PMID: 34773225 DOI: 10.1007/978-3-030-81147-1_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
The circadian clock governs multiple biological functions at the molecular level and plays an essential role in providing temporal diversity of behavior and physiology including neuronal activity. Studies spanning the past two decades have deciphered the molecular mechanisms of the circadian clock, which appears to operate as an essential interface in linking cellular metabolism to epigenetic control. Accumulating evidence illustrates that disruption of circadian rhythms through jet lag, shift work, and temporary irregular life-style could lead to depression-like symptoms. Remarkably, abnormal neuronal activity and depression-like behavior appear in animals lacking elements of the molecular clock. Recent studies demonstrate that neuronal and synaptic gene induction is under epigenetic control, and robust epigenetic remodeling is observed under depression and related psychiatric disorders. Thus, the intertwined links between the circadian clock and epigenetics may point to novel approaches for antidepressant treatments, epigenetic therapy, and chronotherapy. In this chapter we summarize how the circadian clock is involved in neuronal functions and depressive-like behavior and propose that potential strategies for antidepressant therapy by incorporating circadian genomic and epigenetic rewiring of neuronal signaling pathways.
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36
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Samoilova EM, Belopasov VV, Ekusheva EV, Zhang C, Troitskiy AV, Baklaushev VP. Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation. J Pers Med 2021; 11:1050. [PMID: 34834402 PMCID: PMC8620936 DOI: 10.3390/jpm11111050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.
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Affiliation(s)
- Ekaterina M. Samoilova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | | | - Evgenia V. Ekusheva
- Academy of Postgraduate Education of the Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies, FMBA of Russia, 125371 Moscow, Russia;
| | - Chao Zhang
- Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China;
| | - Alexander V. Troitskiy
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | - Vladimir P. Baklaushev
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
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Abstract
ABSTRACT Recent research efforts have provided compelling evidence of genome-wide DNA methylation alterations in pediatrics. It is currently well established that epigenetic clocks, composed of DNA methylation sites, can estimate the gestational and chronological age of cells and tissues from different ages. Also, extensive research is aimed at their correlation with early life exposure and pediatric diseases. This review aimed to systematically summarize the epigenetic clocks in the pediatric population. Publications were collected from PubMed and Web of Science databases up to Apr 2021. Epigenetic clocks, DNA methylation clocks, epigenetic age acceleration or deceleration, pediatric and the pediatric population were used as search criteria. Here, we first review the currently applicative pediatric epigenetic clocks. We then highlight the interpretation for epigenetic age deviations in the pediatric population and their association with external factors, developmental trajectories, and pediatric diseases. Considering the remaining unknown of pediatric clocks, research strategies into them are also discussed. In all, pediatric epigenetic clocks may act as potent tools to understand development, growth and diseases in early life.
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38
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Deshpande SSS, Nemani H, Balasinor NH. High fat diet-induced- and genetically inherited- obesity differential alters DNA demethylation pathways in the germline of adult male rats. Reprod Biol 2021; 21:100532. [PMID: 34246869 DOI: 10.1016/j.repbio.2021.100532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/11/2021] [Accepted: 06/29/2021] [Indexed: 11/17/2022]
Abstract
Obesity is a multifactorial condition with predominantly genetic and environmental causes and is an emerging risk factor for male infertility/subfertility. Epigenetic mechanisms are vulnerable to genetic and environmental changes. Our earlier studies have shown differential effects of genetically inherited (GIO) - and diet-induced- obesity (DIO) on DNA methylation in male germline. Contrary to DNA methylation is DNA demethylation, which also regulates the gene expression by activating transcription. The present study aimed to delineate the effects of obesity on the DNA demethylation pathway using two rat models: GIO (WNIN/Ob) and DIO (high-fat diet). We observed differential alterations in enzymes involved in DNA demethylation by oxidation (Tet1-3) pathway in testis in both groups. An increase in Tets in DIO group and a decrease in GIO group were noted. Analysis of oxidation pathway intermediates (5-hmC, 5-fC, and 5-caC) did not show any effect on testis in DIO group but an increase in 5-hmC and decrease in 5-caC levels in GIO group was observed. Analysis of transcript levels of enzymes related to deamination pathway in testis showed an increase (Gadd45a, Aicda, and Tdg) in DIO group and a decrease (Gadd45a, Aicda, and Tdg) in GIO group. Also, 5-hmC levels were differentially altered in the spermatozoa of both groups without any changes in Tet enzyme levels. These findings highlight differences in effects of GIO and DIO on DNA demethylation mechanisms in male germline, which could be due to differences in endocrine and metabolic profile as well as white fat distribution observed earlier in two groups.
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Affiliation(s)
- Sharvari S S Deshpande
- Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India
| | - Harishankar Nemani
- National Institute of Nutrition Animal Facility, ICMR-National Institute of Nutrition, Jamai-Osmania PO, Hyderabad, 500 007, India
| | - Nafisa H Balasinor
- Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India.
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39
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Vaziri A, Dus M. Brain on food: The neuroepigenetics of nutrition. Neurochem Int 2021; 149:105099. [PMID: 34133954 DOI: 10.1016/j.neuint.2021.105099] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 04/29/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022]
Abstract
Humans have known for millennia that nutrition has a profound influence on health and disease, but it is only recently that we have begun mapping the mechanisms via which the dietary environment impacts brain physiology and behavior. Here we review recent evidence on the effects of energy-dense and methionine diets on neural epigenetic marks, gene expression, and behavior in invertebrate and vertebrate model organisms. We also discuss limitations, open questions, and future directions in the emerging field of the neuroepigenetics of nutrition.
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Affiliation(s)
- Anoumid Vaziri
- Molecular, Cellular and Developmental Biology Graduate Program, The University of Michigan, Ann Arbor, USA; Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor, USA
| | - Monica Dus
- Molecular, Cellular and Developmental Biology Graduate Program, The University of Michigan, Ann Arbor, USA; Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor, USA.
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40
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Lecoutre S, Maqdasy S, Breton C. Maternal obesity as a risk factor for developing diabetes in offspring: An epigenetic point of view. World J Diabetes 2021; 12:366-382. [PMID: 33889285 PMCID: PMC8040079 DOI: 10.4239/wjd.v12.i4.366] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 01/30/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
According to the developmental origin of health and disease concept, the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. In particular, maternal obesity and neonatal accelerated growth predispose offspring to overweight and type 2 diabetes (T2D) in adulthood. This concept mainly relies on the developmental plasticity of adipose tissue and pancreatic β-cell programming in response to suboptimal milieu during the perinatal period. These changes result in unhealthy hypertrophic adipocytes with decreased capacity to store fat, low-grade inflammation and loss of insulin-producing pancreatic β-cells. Over the past years, many efforts have been made to understand how maternal obesity induces long-lasting adipose tissue and pancreatic β-cell dysfunction in offspring and what are the molecular basis of the transgenerational inheritance of T2D. In particular, rodent studies have shed light on the role of epigenetic mechanisms in linking maternal nutritional manipulations to the risk for T2D in adulthood. In this review, we discuss epigenetic adipocyte and β-cell remodeling during development in the progeny of obese mothers and the persistence of these marks as a basis of obesity and T2D predisposition.
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Affiliation(s)
- Simon Lecoutre
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141-86, Sweden
- University of Lille, EA4489, Maternal Malnutrition and Programming of Metabolic Diseases, Lille 59000, France
| | - Salwan Maqdasy
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141-86, Sweden
- Clermont-Ferrand CHU, Department of Endocrinology, Diabetology and Metabolic Diseases, Clermont-Ferrand 63003, France
| | - Christophe Breton
- University of Lille, EA4489, Maternal Malnutrition and Programming of Metabolic Diseases, Lille 59000, France
- U1283-UMR8199-EGID, University of Lille, Institut National de la Santé Et de la Recherche Médicale, Centre National de la Recherche Scientifique, Lille 59000, France
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Nanda P, Ghosh A. Genome Scale-Differential Flux Analysis reveals deregulation of lung cell metabolism on SARS-CoV-2 infection. PLoS Comput Biol 2021; 17:e1008860. [PMID: 33835998 PMCID: PMC8034727 DOI: 10.1371/journal.pcbi.1008860] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/09/2021] [Indexed: 12/27/2022] Open
Abstract
The COVID-19 pandemic is posing an unprecedented threat to the whole world. In this regard, it is absolutely imperative to understand the mechanism of metabolic reprogramming of host human cells by SARS-CoV-2. A better understanding of the metabolic alterations would aid in design of better therapeutics to deal with COVID-19 pandemic. We developed an integrated genome-scale metabolic model of normal human bronchial epithelial cells (NHBE) infected with SARS-CoV-2 using gene-expression and macromolecular make-up of the virus. The reconstructed model predicts growth rates of the virus in high agreement with the experimental measured values. Furthermore, we report a method for conducting genome-scale differential flux analysis (GS-DFA) in context-specific metabolic models. We apply the method to the context-specific model and identify severely affected metabolic modules predominantly comprising of lipid metabolism. We conduct an integrated analysis of the flux-altered reactions, host-virus protein-protein interaction network and phospho-proteomics data to understand the mechanism of flux alteration in host cells. We show that several enzymes driving the altered reactions inferred by our method to be directly interacting with viral proteins and also undergoing differential phosphorylation under diseased state. In case of SARS-CoV-2 infection, lipid metabolism particularly fatty acid oxidation, cholesterol biosynthesis and beta-oxidation cycle along with arachidonic acid metabolism are predicted to be most affected which confirms with clinical metabolomics studies. GS-DFA can be applied to existing repertoire of high-throughput proteomic or transcriptomic data in diseased condition to understand metabolic deregulation at the level of flux. Metabolic flux analysis in disease biology is opening up new avenues for therapeutic interventions. Numerous diseases lead to disturbance in the metabolic homeostasis and it is becoming increasingly important to be able to quantify the difference in interaction under normal and diseased condition. While genome-scale metabolic models have been used to study those differences, there are limited methods to probe into the differences in flux between these two conditions. Our method of conducting a differential flux analysis can be leveraged to find which reactions are altered between the diseased and normal state. We applied this to study the altered reactions in the case of SARS-CoV-2 infection. We further corroborated our results with other multi-omics studies and found significant agreement.
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Affiliation(s)
- Piyush Nanda
- Department of Biotechnology, Indian Institute of Technology Kharagpur, West Bengal, India
| | - Amit Ghosh
- School of Energy Science and Engineering, Indian Institute of Technology Kharagpur, West Bengal, India
- P.K. Sinha Centre for Bioenergy and Renewables, Indian Institute of Technology Kharagpur, West Bengal, India
- * E-mail:
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Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun 2021; 12:1455. [PMID: 33674593 PMCID: PMC7935900 DOI: 10.1038/s41467-021-21804-1] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity. Intratumoral CD8+ T cells commonly display a dysfunctional state, however it remains unclear whether tumor cell metabolism actively promotes T-cell exhaustion. Here, the authors show that the tumor methionine recycling pathway has a central role in promoting T-cell dysfunction in hepatocellular carcinoma, contributing to tumor immune evasion.
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43
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Abstract
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.
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Garnett S, de Bruyns A, Provencher-Tom V, Dutchak K, Shu R, Dankort D. Metabolic Regulator IAPP (Amylin) Is Required for BRAF and RAS Oncogene-Induced Senescence. Mol Cancer Res 2021; 19:874-885. [PMID: 33500359 DOI: 10.1158/1541-7786.mcr-20-0879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/17/2020] [Accepted: 01/21/2021] [Indexed: 11/16/2022]
Abstract
Cellular senescence is characterized by a prolonged and predominantly irreversible cell-cycle arrest state, which is linked to loss of tissue function and aging in mammals. Moreover, in response to aberrant oncogenic signals such as those from oncogenic RAS or BRAF, senescence functions as an intrinsic tumor suppressor mechanism restraining tumor progression. In addition to this durable proliferative block, senescent cells adopt altered morphologies, transcriptional profiles, and metabolism, while often possessing unusual heterochromatin formation termed senescence-associated heterochromatic foci. To uncover genes that are required to permit proliferation in the face of sustained oncogene signaling, we conducted an shRNA-based genetic screen in primary cells expressing inducible BRAF. Here we show that depletion of a known glycolysis regulator, islet amylin polypeptide (IAPP also known as amylin), prevents RAS and BRAF oncogene-induced senescence (OIS) in human cells. Importantly, depletion of IAPP resulted in changes of the cells' metabolome and this metabolic reprogramming was associated with widespread alterations in chromatin modifications compared with senescent cells. Conversely, exogenous treatment of IAPP-depleted cells with amylin restored OIS. Together, our results demonstrate that the metabolic regulator IAPP is important regulator of OIS. Moreover, they suggest that IAPP analog treatment or activation of IAPP signaling in RAS/BRAF mutant tumors may have therapeutic potential through senescence induction. IMPLICATIONS: These findings demonstrate that IAPP is a novel metabolic regulator of oncogene-induced senescence and use of IAPP analogs may be therapeutically effective to restore growth arrest to BRAF and/or RAS mutant cancers.
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Affiliation(s)
- Sam Garnett
- Department of Biology, McGill University, Montréal QC, Canada
| | | | | | - Kendall Dutchak
- Department of Biology, McGill University, Montréal QC, Canada
| | - Ran Shu
- Department of Biology, McGill University, Montréal QC, Canada
| | - David Dankort
- Department of Biology, McGill University, Montréal QC, Canada. .,Goodman Cancer Research Centre, Montréal QC, Canada
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Millan-Ariño L, Yuan ZF, Oomen ME, Brandenburg S, Chernobrovkin A, Salignon J, Körner L, Zubarev RA, Garcia BA, Riedel CG. Histone Purification Combined with High-Resolution Mass Spectrometry to Examine Histone Post-Translational Modifications and Histone Variants in Caenorhabditis elegans. ACTA ACUST UNITED AC 2021; 102:e114. [PMID: 32997895 PMCID: PMC7583481 DOI: 10.1002/cpps.114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Histones are the major proteinaceous component of chromatin in eukaryotic cells and an important part of the epigenome, affecting most DNA‐related events, including transcription, DNA replication, and chromosome segregation. The properties of histones are greatly influenced by their post‐translational modifications (PTMs), over 200 of which are known today. Given this large number, researchers need sophisticated methods to study histone PTMs comprehensively. In particular, mass spectrometry (MS)−based approaches have gained popularity, allowing for the quantification of dozens of histone PTMs at once. Using these approaches, even the study of co‐occurring PTMs and the discovery of novel PTMs become feasible. The success of MS‐based approaches relies substantially on obtaining pure and well‐preserved histones for analysis, which can be difficult depending on the source material. Caenorhabditis elegans has been a popular model organism to study the epigenome, but isolation of pure histones from these animals has been challenging. Here, we address this issue, presenting a method for efficient isolation of pure histone proteins from C. elegans at good yield. Further, we describe an MS pipeline optimized for accurate relative quantification of histone PTMs from C. elegans. We alkylate and tryptically digest the histones, analyze them by bottom‐up MS, and then evaluate the resulting data by a C. elegans−adapted version of the software EpiProfile 2.0. Finally, we show the utility of this pipeline by determining differences in histone PTMs between C. elegans strains that age at different rates and thereby achieve very different lifespans. © 2020 The Authors. Basic Protocol 1: Large‐scale growth and harvesting of synchronized C. elegans Basic Protocol 2: Nuclear preparation, histone extraction, and histone purification Basic Protocol 3: Bottom‐up mass spectrometry analysis of histone PTMs and histone variants
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Affiliation(s)
- Lluís Millan-Ariño
- Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institute, Huddinge, Sweden.,Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Zuo-Fei Yuan
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Marlies E Oomen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - Simone Brandenburg
- European Research Institute for the Biology of Ageing, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - Alexey Chernobrovkin
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden
| | - Jérôme Salignon
- Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institute, Huddinge, Sweden.,Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Lioba Körner
- Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institute, Huddinge, Sweden.,Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Roman A Zubarev
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden.,Department of Pharmacological & Technological Chemistry, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Benjamin A Garcia
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christian G Riedel
- Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institute, Huddinge, Sweden.,Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.,European Research Institute for the Biology of Ageing, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
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Ming X, Zhu B, Li Y. Mitotic inheritance of DNA methylation: more than just copy and paste. J Genet Genomics 2021; 48:1-13. [PMID: 33771455 DOI: 10.1016/j.jgg.2021.01.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/13/2021] [Accepted: 01/22/2021] [Indexed: 12/14/2022]
Abstract
Decades of investigation on DNA methylation have led to deeper insights into its metabolic mechanisms and biological functions. This understanding was fueled by the recent development of genome editing tools and our improved capacity for analyzing the global DNA methylome in mammalian cells. This review focuses on the maintenance of DNA methylation patterns during mitotic cell division. We discuss the latest discoveries of the mechanisms for the inheritance of DNA methylation as a stable epigenetic memory. We also highlight recent evidence showing the rapid turnover of DNA methylation as a dynamic gene regulatory mechanism. A body of work has shown that altered DNA methylomes are common features in aging and disease. We discuss the potential links between methylation maintenance mechanisms and disease-associated methylation changes.
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Affiliation(s)
- Xuan Ming
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Bing Zhu
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Yingfeng Li
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
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Aly J, Engmann O. The Way to a Human's Brain Goes Through Their Stomach: Dietary Factors in Major Depressive Disorder. Front Neurosci 2020; 14:582853. [PMID: 33364919 PMCID: PMC7750481 DOI: 10.3389/fnins.2020.582853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
Globally, more than 250 million people are affected by depression (major depressive disorder; MDD), a serious and debilitating mental disorder. Currently available treatment options can have substantial side effects and take weeks to be fully effective. Therefore, it is important to find safe alternatives, which act more rapidly and in a larger number of patients. While much research on MDD focuses on chronic stress as a main risk factor, we here make a point of exploring dietary factors as a somewhat overlooked, yet highly promising approach towards novel antidepressant pathways. Deficiencies in various groups of nutrients often occur in patients with mental disorders. These include vitamins, especially members of the B-complex (B6, B9, B12). Moreover, an imbalance of fatty acids, such as omega-3 and omega-6, or an insufficient supply with minerals, including magnesium and zinc, are related to MDD. While some of them are relevant for the synthesis of monoamines, others play a crucial role in inflammation, neuroprotection and the synthesis of growth factors. Evidence suggests that when deficiencies return to normal, changes in mood and behavior can be, at least in some cases, achieved. Furthermore, supplementation with dietary factors (so called "nutraceuticals") may improve MDD symptoms even in the absence of a deficiency. Non-vital dietary factors may affect MDD symptoms as well. For instance, the most commonly consumed psychostimulant caffeine may improve behavioral and molecular markers of MDD. The molecular structure of most dietary factors is well known. Hence, dietary factors may provide important molecular tools to study and potentially help treat MDD symptoms. Within this review, we will discuss the role of dietary factors in MDD risk and symptomology, and critically discuss how they might serve as auxiliary treatments or preventative options for MDD.
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Affiliation(s)
- Janine Aly
- Faculty of Medicine, Friedrich Schiller Universität, Jena, Germany
| | - Olivia Engmann
- Institute for Human Genetics, Jena University Hospital, Jena, Germany
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Lecoutre S, Maqdasy S, Petrus P, Ludzki A, Couchet M, Mejhert N, Rydén M. Glutamine metabolism in adipocytes: a bona fide epigenetic modulator of inflammation. Adipocyte 2020; 9:620-625. [PMID: 33043853 PMCID: PMC7553504 DOI: 10.1080/21623945.2020.1831825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A chronic low-grade inflammation of white adipose tissue (WAT) is one of the hallmarks of obesity and is proposed to contribute to insulin resistance and type 2 diabetes. Despite this, the causal mechanisms underlying WAT inflammation remain unclear. Based on metabolomic analyses of human WAT, Petrus et al. showed that the amino acid glutamine was the most markedly reduced polar metabolite in the obese state. Reduced glutamine levels in adipocytes induce an increase of Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) levels via induction of glycolysis and the hexosamine biosynthetic pathways. This promotes nuclear O-GlcNAcylation, a posttranslational modification that activates the transcription of pro-inflammatory genes. Conversely, glutamine supplementation in vitro and in vivo, reversed these effects. Altogether, dysregulation of intracellular glutamine metabolism in WAT establishes an epigenetic link between adipocytes and inflammation. This commentary discusses these findings and their possibly therapeutic relevance in relation to insulin resistance and type 2 diabetes.
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Affiliation(s)
- Simon Lecoutre
- Department of Medicine (H7), Karolinska University Hospital, Stockholm, Sweden
| | - Salwan Maqdasy
- Department of Medicine (H7), Karolinska University Hospital, Stockholm, Sweden
- CHU Clermont-Ferrand, Service D’endocrinologie, Diabétologie et Maladies Métaboliques, Clermont-Ferrand, France
- Faculté de Médecine, Laboratoire GReD, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Paul Petrus
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, INSERM U1233, University of California, Irvine, CA, USA
| | - Alison Ludzki
- Department of Medicine (H7), Karolinska University Hospital, Stockholm, Sweden
| | - Morgane Couchet
- Department of Medicine (H7), Karolinska University Hospital, Stockholm, Sweden
| | - Niklas Mejhert
- Department of Medicine (H7), Karolinska University Hospital, Stockholm, Sweden
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska University Hospital, Stockholm, Sweden
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Deshpande SS, Nemani H, Arumugam G, Ravichandran A, Balasinor NH. High-fat diet-induced and genetically inherited obesity differentially alters DNA methylation profile in the germline of adult male rats. Clin Epigenetics 2020; 12:179. [PMID: 33213487 PMCID: PMC7678167 DOI: 10.1186/s13148-020-00974-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/10/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Paternal obesity has been associated with reduced live birth rates. It could lead to inheritance of metabolic disturbances to the offspring through epigenetic mechanisms. However, obesity is a multifactorial disorder with genetic or environmental causes. Earlier we had demonstrated differential effects of high-fat diet-induced obesity (DIO) and genetically inherited obesity (GIO) on metabolic, hormonal profile, male fertility, and spermatogenesis using two rat models. The present study aimed to understand the effect of DIO and GIO on DNA methylation in male germline, and its subsequent effects on the resorbed (post-implantation embryo loss) and normal embryos. First, we assessed the DNA methylation enzymatic machinery in the testis by Real-Time PCR, followed global DNA methylation levels in spermatozoa and testicular cells by ELISA and flow cytometry, respectively. Further, we performed Methylation Sequencing in spermatozoa for both the groups. Sequencing data in spermatozoa from both the groups were validated using Pyrosequencing. Expression of the differentially methylated genes was assessed in the resorbed and normal embryos sired by the DIO group using Real-Time PCR for functional validation. RESULTS We noted a significant decrease in Dnmt transcript and global DNA methylation levels in the DIO group and an increase in the GIO group. Sequencing analysis showed 16,966 and 9113 differentially methylated regions in the spermatozoa of the DIO and GIO groups, respectively. Upon pathway analysis, we observed genes enriched in pathways involved in embryo growth and development namely Wnt, Hedgehog, TGF-beta, and Notch in spermatozoa for both the groups, the methylation status of which partially correlated with the gene expression pattern in resorbed and normal embryos sired by the DIO group. CONCLUSION Our study reports the mechanism by which diet-induced and genetically inherited obesity causes differential effects on the DNA methylation in the male germline that could be due to a difference in the white adipose tissue accumulation. These differences could either lead to embryo loss or transmit obesity-related traits to the offspring in adult life.
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Affiliation(s)
- Sharvari S. Deshpande
- Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai 400012 India
| | - Harishankar Nemani
- National Institute of Nutrition Animal Facility, ICMR-National Institute of Nutrition, Jamai-Osmania PO, Hyderabad 500 007 India
| | - Gandhimathi Arumugam
- Genome Informatics Department, Genotypic Technologies Pvt. Ltd., #2/13, Balaji Complex, Poojari Layout, 80 Feet Road, R.M.V. 2nd stage, Bengaluru, India
| | - Avinash Ravichandran
- Genome Informatics Department, Genotypic Technologies Pvt. Ltd., #2/13, Balaji Complex, Poojari Layout, 80 Feet Road, R.M.V. 2nd stage, Bengaluru, India
| | - Nafisa H. Balasinor
- Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai 400012 India
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50
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Götting I, Jendrossek V, Matschke J. A New Twist in Protein Kinase B/Akt Signaling: Role of Altered Cancer Cell Metabolism in Akt-Mediated Therapy Resistance. Int J Mol Sci 2020; 21:ijms21228563. [PMID: 33202866 PMCID: PMC7697684 DOI: 10.3390/ijms21228563] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/23/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer resistance to chemotherapy, radiotherapy and molecular-targeted agents is a major obstacle to successful cancer therapy. Herein, aberrant activation of the phosphatidyl-inositol-3-kinase (PI3K)/protein kinase B (Akt) pathway is one of the most frequently deregulated pathways in cancer cells and has been associated with multiple aspects of therapy resistance. These include, for example, survival under stress conditions, apoptosis resistance, activation of the cellular response to DNA damage and repair of radiation-induced or chemotherapy-induced DNA damage, particularly DNA double strand breaks (DSB). One further important, yet not much investigated aspect of Akt-dependent signaling is the regulation of cell metabolism. In fact, many Akt target proteins are part of or involved in the regulation of metabolic pathways. Furthermore, recent studies revealed the importance of certain metabolites for protection against therapy-induced cell stress and the repair of therapy-induced DNA damage. Thus far, the likely interaction between deregulated activation of Akt, altered cancer metabolism and therapy resistance is not yet well understood. The present review describes the documented interactions between Akt, its target proteins and cancer cell metabolism, focusing on antioxidant defense and DSB repair. Furthermore, the review highlights potential connections between deregulated Akt, cancer cell metabolism and therapy resistance of cancer cells through altered DSB repair and discusses potential resulting therapeutic implications.
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