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Sharma P, Mohanty S, Ahmad Y. Decoding Proteomic cross-talk between hypobaric and normobaric hypoxia: Integrative analysis of oxidative stress, cytoskeleton remodeling, and inflammatory pathways. Life Sci 2025; 371:123611. [PMID: 40187642 DOI: 10.1016/j.lfs.2025.123611] [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: 12/26/2024] [Revised: 03/22/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
AIMS To investigate the differential regulation of proteomic landscapes elicited by hypobaric hypoxia (HH) and normobaric hypoxia (NH) and to shed light on the molecular cross-talk underlying pre-acclimatization strategies. MATERIALS AND METHODS Label-free LCMS-MS quantitative proteomics was employed to evaluate the lung tissues of SD rats (n = 6) subjected to 6 h of acute HH at 25,000 ft associated with reduced barometric pressure, 282 mmHg, and NH at 8 % FiO2. KEY FINDINGS Our findings indicate that NH facilitated the minimal downregulation of proteins involved in maintaining pulmonary cytoskeleton integrity, including calpain 2, vitronectin, and beta-arrestin 1, whereas HH leads to severe downregulation of these proteins, causing a greater cytoskeleton disruption. Proteins contributing to redox homeostasis such as iNOS and SOD, were upregulated in both hypoxic conditions. However, SIRT1-mediated ROS-triggered proteins, including FOXO1 and FOXO4, exhibited upregulation in HH and downregulation in NH. Other proteins, HIF-1α and IDH, were upregulated in HH compared to NH. Additionally, Hemopexin was severely downregulated in HH relative to NH. SIGNIFICANCE For the first time, this study uncovers the comparative proteomic analysis of two distinct pre-acclimatization interventions by employing varied hypoxia modeling strategies highlighting the key molecular mechanism involved in HH acclimatization induced by differential hypoxia simulating technique.
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Affiliation(s)
- Poornima Sharma
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
| | - Swaraj Mohanty
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
| | - Yasmin Ahmad
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India.
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2
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Kzar WA, Abbas RF. Association of Polymorphism with Periodontitis and Salivary Levels of Hypoxia-Inducible Factor-1α. Eur J Dent 2025; 19:133-143. [PMID: 38744330 PMCID: PMC11750348 DOI: 10.1055/s-0044-1785530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2024] Open
Abstract
OBJECTIVE This investigation aims to investigate the association between HIF-1α genetic polymorphism and periodontitis and examine and contrast the levels of HIF-1α present in the saliva of subjects afflicted with periodontitis and in the control group. Additionally, this study aims to establish diagnostic proficiency of this biomarker in distinguishing between periodontal health and disease. MATERIALS AND METHODS This study entailed the collection of venous blood samples and unstimulated saliva samples from a total of 160 participants, encompassing 80 individuals diagnosed with periodontitis and 80 periodontitis-free individuals. The periodontal parameters were evaluated, involving the measurement of clinical attachment loss, the probing pocket depth, and the bleeding on probing percentage. Subsequently, genetic analysis of HIF-1α using polymerase chain reaction (PCR) technique, DNA sequencing, and enzyme-linked immunosorbent assays was conducted. RESULTS The genetic analysis of 352 bp of the HIF-1α gene revealed the presence of 66 single-nucleotide polymorphisms (SNPs) in control samples, whereas 78 SNPs were found in periodontitis sample. The nucleotide A was replaced with a C nucleotide at position 207 of the amplified PCR fragments. The homozygous AA pattern was predominant in the control group, with significant differences between the two groups. In contrast, the homozygous CC pattern was more dominant in the periodontitis group, with significant differences between the two groups. The analysis of Hardy-Weinberg equilibrium for the comparison between the observed and the expected genotypes showed significant differences between the observed and the expected values in the control and periodontitis groups, as well as the total sample. The highest mean values of the measured periodontal parameters were found in the periodontitis group (clinical attachment loss = 4.759, probing pocket depth = 4.050, and bleeding on probing = 30.950) with statistically significant differences between the groups. The periodontitis group showed significantly higher salivary HIF-1α levels compared to control group (p < 0.001). Besides, HIF-1α is a good biomarker in distinguishing between periodontal health and periodontitis. CONCLUSION rs1951795 SNP of HIF-1α has no significant impact on the progression of periodontitis and the salivary level HIF-1α. Periodontitis results in a notable elevation in HIF-1α salivary levels, with an outstanding diagnostic ability to distinguish between periodontitis and periodontal health.
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Affiliation(s)
- Wael Abdulazeez Kzar
- Department of Periodontology, College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Raghad Fadhil Abbas
- Department of Periodontology, College of Dentistry, University of Baghdad, Baghdad, Iraq
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3
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Colombi D, Perini F, Bettini S, Mastrangelo S, Abeni F, Conte G, Marletta D, Cassandro M, Bernabucci U, Ciampolini R, Lasagna E. Genomic responses to climatic challenges in beef cattle: A review. Anim Genet 2024; 55:854-870. [PMID: 39219301 DOI: 10.1111/age.13474] [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: 05/13/2024] [Revised: 07/31/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Climate change is a major concern for the near future and for livestock breeding. Cattle breeding, due to its greenhouse gas emissions, is one of the most implicated industries. Consequently, the main future goals are to breed animals resilient to climate change, with the aim of lowering the livestock impact on the environment and selecting animals that will be able to resist different, unsuitable, and changing climates. The aim of this literature review is to compare the most recent studies on the response and adaptation of beef cattle breeds to extreme environments, in terms of genes and pathways involved. Beef breeding is just starting to implement genomics in its selection plans, and shedding light on the genomic responses to extreme climates could speed up and simplify the adaptation of these breeds to climate change. This review discusses the genes involved in climatic stress responses, including those related to extremely cold climates, in beef and dual-purpose cattle breeds. Genes were associated with productive traits, coat and skin structure and development, thermotolerance, cellular physiology and DNA repair mechanisms, immune system, and fertility traits. The knowledge of genes and pathways involved in climate resilience should be taken into consideration for further selection in beef cattle breeding and could promote the valorization of local breeds adapted to extreme environmental conditions. The use of local or resilient breeds could enhance the environmental and social sustainability, animal welfare, and production, compared with the introduction of cosmopolitan breeds with uncertain adaptation in uncontrolled environmental areas.
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Affiliation(s)
- Daniele Colombi
- Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia, Italy
| | - Francesco Perini
- Department of Agronomy, Food, Natural Resources, Animals and Environment, University of Padova, Legnaro, Italy
| | - Stefano Bettini
- Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia, Italy
| | - Salvatore Mastrangelo
- Department of Agricultural, Food and Forest Sciences, University of Palermo, Palermo, Italy
| | - Fabio Abeni
- Centro di Ricerca Zootecnia e Acquacoltura, Consiglio per la Ricerca in Agricoltura e l'Analisi dell'Economia Agraria (CREA), Lodi, Italy
| | - Giuseppe Conte
- Department of Agriculture, Food and Environment, University of Pisa, Pisa, Italy
- Interuniversity Center for Adaptability of Livestock Systems to Climate Change (ASIZOCACLI), Catania, Italy
| | - Donata Marletta
- Interuniversity Center for Adaptability of Livestock Systems to Climate Change (ASIZOCACLI), Catania, Italy
- Department of Agriculture, Food and Environment, University of Catania, Catania, Italy
| | - Martino Cassandro
- Department of Agronomy, Food, Natural Resources, Animals and Environment, University of Padova, Legnaro, Italy
- Interuniversity Center for Adaptability of Livestock Systems to Climate Change (ASIZOCACLI), Catania, Italy
| | - Umberto Bernabucci
- Interuniversity Center for Adaptability of Livestock Systems to Climate Change (ASIZOCACLI), Catania, Italy
- Department of Agriculture and Forest Sciences, Università Della Tuscia, Viterbo, Italy
| | - Roberta Ciampolini
- Interuniversity Center for Adaptability of Livestock Systems to Climate Change (ASIZOCACLI), Catania, Italy
- Department of Veterinary Sciences, University of Pisa, Pisa, Italy
| | - Emiliano Lasagna
- Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia, Italy
- Interuniversity Center for Adaptability of Livestock Systems to Climate Change (ASIZOCACLI), Catania, Italy
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4
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Rey-Keim S, Schito L. Origins and molecular effects of hypoxia in cancer. Semin Cancer Biol 2024; 106-107:166-178. [PMID: 39427969 DOI: 10.1016/j.semcancer.2024.10.001] [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: 08/09/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 10/22/2024]
Abstract
Hypoxia (insufficient O2) is a pivotal factor in cancer progression, triggering genetic, transcriptional, translational and epigenetic adaptations associated to therapy resistance, metastasis and patient mortality. In this review, we outline the microenvironmental origins and molecular mechanisms responsible for hypoxic cancer cell adaptations in situ and in vitro, whilst outlining current approaches to stratify, quantify and therapeutically target hypoxia in the context of precision oncology.
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Affiliation(s)
- Sergio Rey-Keim
- UCD School of Medicine, University College Dublin, Belfield, Dublin D04 C7X2, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 C7X2, Ireland.
| | - Luana Schito
- UCD School of Medicine, University College Dublin, Belfield, Dublin D04 C7X2, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 C7X2, Ireland.
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5
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Sjodin BMF, Schmidt DA, Galbreath KE, Russello MA. Putative climate adaptation in American pikas (Ochotona princeps) is associated with copy number variation across environmental gradients. Sci Rep 2024; 14:8568. [PMID: 38609461 PMCID: PMC11014952 DOI: 10.1038/s41598-024-59157-6] [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: 11/17/2023] [Accepted: 04/08/2024] [Indexed: 04/14/2024] Open
Abstract
Improved understanding of the genetic basis of adaptation to climate change is necessary for maintaining global biodiversity moving forward. Studies to date have largely focused on sequence variation, yet there is growing evidence that suggests that changes in genome structure may be an even more significant source of adaptive potential. The American pika (Ochotona princeps) is an alpine specialist that shows some evidence of adaptation to climate along elevational gradients, but previous work has been limited to single nucleotide polymorphism based analyses within a fraction of the species range. Here, we investigated the role of copy number variation underlying patterns of local adaptation in the American pika using genome-wide data previously collected across the entire species range. We identified 37-193 putative copy number variants (CNVs) associated with environmental variation (temperature, precipitation, solar radiation) within each of the six major American pika lineages, with patterns of divergence largely following elevational and latitudinal gradients. Genes associated (n = 158) with independent annotations across lineages, variables, and/or CNVs had functions related to mitochondrial structure/function, immune response, hypoxia, olfaction, and DNA repair. Some of these genes have been previously linked to putative high elevation and/or climate adaptation in other species, suggesting they may serve as important targets in future studies.
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Affiliation(s)
- Bryson M F Sjodin
- Department of Biology, The University of British Columbia, 3247 University Way, Kelowna, BC, V1V 1V7, Canada
| | - Danielle A Schmidt
- Department of Biology, The University of British Columbia, 3247 University Way, Kelowna, BC, V1V 1V7, Canada
| | - Kurt E Galbreath
- Department of Biology, Northern Michigan University, 1401 Presque Isle Ave, Marquette, MI, 49855, USA
| | - Michael A Russello
- Department of Biology, The University of British Columbia, 3247 University Way, Kelowna, BC, V1V 1V7, Canada.
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Foucault L, Capeliez T, Angonin D, Lentini C, Bezin L, Heinrich C, Parras C, Donega V, Marcy G, Raineteau O. Neonatal brain injury unravels transcriptional and signaling changes underlying the reactivation of cortical progenitors. Cell Rep 2024; 43:113734. [PMID: 38349790 DOI: 10.1016/j.celrep.2024.113734] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/03/2023] [Accepted: 01/16/2024] [Indexed: 02/15/2024] Open
Abstract
Germinal activity persists throughout life within the ventricular-subventricular zone (V-SVZ) of the postnatal forebrain due to the presence of neural stem cells (NSCs). Accumulating evidence points to a recruitment for these cells following early brain injuries and suggests their amenability to manipulations. We used chronic hypoxia as a rodent model of early brain injury to investigate the reactivation of cortical progenitors at postnatal times. Our results reveal an increased proliferation and production of glutamatergic progenitors within the dorsal V-SVZ. Fate mapping of V-SVZ NSCs demonstrates their contribution to de novo cortical neurogenesis. Transcriptional analysis of glutamatergic progenitors shows parallel changes in methyltransferase 14 (Mettl14) and Wnt/β-catenin signaling. In agreement, manipulations through genetic and pharmacological activation of Mettl14 and the Wnt/β-catenin pathway, respectively, induce neurogenesis and promote newly-formed cell maturation. Finally, labeling of young adult NSCs demonstrates that pharmacological NSC activation has no adverse effects on the reservoir of V-SVZ NSCs and on their germinal activity.
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Affiliation(s)
- Louis Foucault
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.
| | - Timothy Capeliez
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
| | - Diane Angonin
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
| | - Celia Lentini
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
| | - Laurent Bezin
- University Lyon, Université Claude Bernard Lyon 1, INSERM, Centre de Recherche en Neuroscience de Lyon U1028 - CNRS UMR5292, 69500 Bron, France
| | - Christophe Heinrich
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
| | - Carlos Parras
- Paris Brain Institute, Sorbonne Université, INSERM U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, 75013 Paris, France
| | - Vanessa Donega
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France; Amsterdam Neuroscience, Cellular and Molecular Mechanisms, Amsterdam, the Netherlands
| | - Guillaume Marcy
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
| | - Olivier Raineteau
- University Lyon, Université Claude Bernard Lyon1, INSERM, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.
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Fok M, Hill R, Fowler H, Clifford R, Kler A, Uzzi-Daniel J, Rocha S, Grundy G, Parsons J, Vimalachandran D. Enhancing radiotherapy outcomes in rectal cancer: A systematic review of targeting hypoxia-induced radioresistance. Clin Transl Radiat Oncol 2024; 44:100695. [PMID: 37961749 PMCID: PMC10637894 DOI: 10.1016/j.ctro.2023.100695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Introduction Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is strong evidence to show that the phenomenon of tumour hypoxia is associated with radioresistance, however the mechanism(s) behind this are poorly understood. Consequently, there have only been a small number of studies evaluating methods targeting hypoxia-induced radioresistance. The purpose of this systematic review is to evaluate the potential effectiveness of targeting hypoxia-induced radioresistance in rectal cancer and provide recommendations for future research in this area. Methods A comprehensive literature search was performed following the PRISMA guidelines. This study was registered on the Prospero database (CRD42023441983). Results Eight articles met the inclusion criteria. All studies identified were in vitro or in vivo studies, there were no clinical trials. Of the 8 studies identified, 5 assessed the efficacy of drugs which directly or indirectly targeted hypoxia and three that identified potential targets. There was conflicting in vivo evidence for the use of metformin to overcome hypoxia induced radioresistance. Vorinostat, atovaquone, and evofosfamide showed promising preclinical evidence that they can overcome hypoxia-induced radioresistance. Discussion The importance of investigating hypoxia-induced radioresistance in rectal cancer is crucial. However, to date, only a small number of preclinical studies exist evaluating this phenomenon. This systematic review highlights the importance of further research to fully understand the mechanism behind this radioresistance. There are promising targets identified in this systematic review however, substantially more pre-clinical and clinical research as a priority for future research is needed.
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Affiliation(s)
- Matthew Fok
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Rhianna Hill
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Hayley Fowler
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Rachael Clifford
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Aaron Kler
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Jayanma Uzzi-Daniel
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Sonia Rocha
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Gabrielle Grundy
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
| | - Jason Parsons
- Institute of Cancer and Genomic Sciences, University of Birmingham, UK
| | - Dale Vimalachandran
- Institute of Systems, Molecular and Integrative Biology University of Liverpool, UK
- Countess of Chester Hospital, Colorectal Surgery Department, Chester, UK
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8
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Kietzmann T. Vitamin C: From nutrition to oxygen sensing and epigenetics. Redox Biol 2023; 63:102753. [PMID: 37263060 PMCID: PMC10245123 DOI: 10.1016/j.redox.2023.102753] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023] Open
Abstract
Vitamin C is unbeatable - at least when it comes to sales. Of all the vitamin preparations, those containing vitamin C sell best. This is surprising because vitamin C deficiency is extremely rare. Nevertheless, there is still controversy about whether the additional intake of vitamin C supplements is essential for our health. In this context, the possible additional benefit is in most cases merely reduced to the known effect as an antioxidant. However, new findings in recent years on the mechanisms of oxygen-sensing and epigenetic control underpin the multifaceted role of vitamin C in a biological context and have therefore renewed interest in it. In the present article, therefore, known facts are linked to these new key data. In addition, available clinical data on vitamin C use of cancer therapy are summarized.
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Affiliation(s)
- Thomas Kietzmann
- University of Oulu, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, P.O. Box 3000, 90014, Oulu, Finland.
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9
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Lv R, Liu X, Zhang Y, Dong N, Wang X, He Y, Yue H, Yin Q. Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome. Signal Transduct Target Ther 2023; 8:218. [PMID: 37230968 DOI: 10.1038/s41392-023-01496-3] [Citation(s) in RCA: 136] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 05/27/2023] Open
Abstract
Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea. The prevalence of OSAS continues to rise worldwide, particularly in middle-aged and elderly individuals. The mechanism of upper airway collapse is incompletely understood but is associated with several factors, including obesity, craniofacial changes, altered muscle function in the upper airway, pharyngeal neuropathy, and fluid shifts to the neck. The main characteristics of OSAS are recurrent pauses in respiration, which lead to intermittent hypoxia (IH) and hypercapnia, accompanied by blood oxygen desaturation and arousal during sleep, which sharply increases the risk of several diseases. This paper first briefly describes the epidemiology, incidence, and pathophysiological mechanisms of OSAS. Next, the alterations in relevant signaling pathways induced by IH are systematically reviewed and discussed. For example, IH can induce gut microbiota (GM) dysbiosis, impair the intestinal barrier, and alter intestinal metabolites. These mechanisms ultimately lead to secondary oxidative stress, systemic inflammation, and sympathetic activation. We then summarize the effects of IH on disease pathogenesis, including cardiocerebrovascular disorders, neurological disorders, metabolic diseases, cancer, reproductive disorders, and COVID-19. Finally, different therapeutic strategies for OSAS caused by different causes are proposed. Multidisciplinary approaches and shared decision-making are necessary for the successful treatment of OSAS in the future, but more randomized controlled trials are needed for further evaluation to define what treatments are best for specific OSAS patients.
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Affiliation(s)
- Renjun Lv
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Xueying Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Yue Zhang
- Department of Geriatrics, the 2nd Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Na Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Xiao Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yao He
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Hongmei Yue
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
| | - Qingqing Yin
- Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
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Luo P, Zhang YD, He F, Tong CJ, Liu K, Liu H, Zhu SZ, Luo JZ, Yuan B. HIF-1α-mediated augmentation of miRNA-18b-5p facilitates proliferation and metastasis in osteosarcoma through attenuation PHF2. Sci Rep 2022; 12:10398. [PMID: 35729160 PMCID: PMC9213540 DOI: 10.1038/s41598-022-13660-w] [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: 12/20/2021] [Accepted: 03/29/2022] [Indexed: 11/09/2022] Open
Abstract
Extensive evidence has explored the involvement of microRNAs (miRNAs) in osteosarcoma (OS). Limitedly, the concrete function of microRNA-18b-5p (miR-18b-5p) in OS remains unexplored and largely elusive. Here, we validated that miR-18b-5p significantly elevated in OS via analyzing the data from GEO database. The results showed that miR-18b-5p was overexpressed in human OS tissues and cell lines. The clinical evidence suggested that high level of miR-18b-5p was negatively correlated with the poor prognosis of OS. Meanwhile, miR-18b-5p upregulation facilitated the proliferation and metastasis of OS cells in vitro and in vivo. The mechanism exploration demonstrated that miR-18b-5p acted as a potential inhibitor of PHF2, a tumor suppressor gene, at post-transcriptional level. Moreover, hypoxia induced gene expression of miR-18b-5p was clarified to be transcriptionally mediated by HIF-1α. The clinicopathological analysis in samples of OS patients further supported that miR-18b-5p had a positive correlation with HIF-1α expression, and negative correlation with PHF2. Collectively, the present study uncovered a new molecular mechanism of OS tumorigenesis and development and miR-18b-5p might be a prognostic biomarker and potential therapeutic target for OS treatment.
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Affiliation(s)
- Peng Luo
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China
| | | | - Feng He
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China
| | - Chang-Jun Tong
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China
| | - Kai Liu
- Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - He Liu
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China
| | - Shi-Zhuang Zhu
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China
| | - Jian-Zhou Luo
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China
| | - Bing Yuan
- Department of Orthopedics, The Fifth Hospital of Wuhan/The Second Affiliated Hospital of Jianghan University, Wuhan, 430050, China.
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11
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Schmidt A, Fuchs M, Stojanović SD, Liang C, Schmidt K, Jung M, Xiao K, Weusthoff J, Just A, Pfanne A, Distler JHW, Dandekar T, Fiedler J, Thum T, Kunz M. Deciphering Pro-angiogenic Transcription Factor Profiles in Hypoxic Human Endothelial Cells by Combined Bioinformatics and in vitro Modeling. Front Cardiovasc Med 2022; 9:877450. [PMID: 35783871 PMCID: PMC9247153 DOI: 10.3389/fcvm.2022.877450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/23/2022] [Indexed: 11/29/2022] Open
Abstract
Background Constant supply of oxygen is crucial for multicellular tissue homeostasis and energy metabolism in cardiac tissue. As a first response to acute hypoxia, endothelial cells (ECs) promote recruitment and adherence of immune cells to the dysbalanced EC barrier by releasing inflammatory mediators and growth factors, whereas chronic hypoxia leads to the activation of a transcription factor (TF) battery, that potently induces expression of growth factors and cytokines including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). We report a hypoxia-minded, targeted bioinformatics approach aiming to identify and validate TFs that regulate angiogenic signaling. Results A comprehensive RNA-Seq dataset derived from human ECs subjected to normoxic or hypoxic conditions was selected to identify significantly regulated genes based on (i) fold change (normoxia vs. hypoxia) and (ii) relative abundancy. Transcriptional regulation of this gene set was confirmed via qPCR in validation experiments where HUVECs were subjected to hypoxic conditions for 24 h. Screening the promoter and upstream regulatory elements of these genes identified two TFs, KLF5 and SP1, both with a potential binding site within these regions of selected target genes. In vitro, siRNA experiments confirmed SP1- and KLF5-mediated regulation of identified hypoxia-sensitive endothelial genes. Next to angiogenic signaling, we also validated the impact of TFs on inflammatory signaling, both key events in hypoxic sensing. Both TFs impacted on inflammatory signaling since endogenous repression led to increased NF-κB signaling. Additionally, SP1 silencing eventuated decreased angiogenic properties in terms of proliferation and tube formation. Conclusion By detailed in silico analysis of promoter region and upstream regulatory elements for a list of hypoxia-sensitive genes, our bioinformatics approach identified putative binding sites for TFs of SP or KLF family in vitro. This strategy helped to identify TFs functionally involved in human angiogenic signaling and therefore serves as a base for identifying novel RNA-based drug entities in a therapeutic setting of vascularization.
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Affiliation(s)
- Arne Schmidt
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Maximilian Fuchs
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Stevan D. Stojanović
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Department of Cardiology and Angiology, Hannover Medical School, Hanover, Germany
| | - Chunguang Liang
- Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Kevin Schmidt
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Mira Jung
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
| | - Ke Xiao
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Jan Weusthoff
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Annette Just
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
| | - Angelika Pfanne
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
| | - Jörg H. W. Distler
- Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Dandekar
- Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Jan Fiedler
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
- Jan Fiedler,
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
- Thomas Thum,
| | - Meik Kunz
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hanover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
- Chair of Medical Informatics, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Meik Kunz,
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12
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Azad P, Caldwell AB, Ramachandran S, Spann NJ, Akbari A, Villafuerte FC, Bermudez D, Zhao H, Poulsen O, Zhou D, Bafna V, Subramaniam S, Haddad GG. ARID1B, a molecular suppressor of erythropoiesis, is essential for the prevention of Monge's disease. Exp Mol Med 2022; 54:777-787. [PMID: 35672450 PMCID: PMC9256584 DOI: 10.1038/s12276-022-00769-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/10/2022] [Accepted: 02/14/2022] [Indexed: 11/09/2022] Open
Abstract
At high altitude Andean region, hypoxia-induced excessive erythrocytosis (EE) is the defining feature of Monge's disease or chronic mountain sickness (CMS). At the same altitude, resides a population that has developed adaptive mechanism(s) to constrain this hypoxic response (non-CMS). In this study, we utilized an in vitro induced pluripotent stem cell model system to study both populations using genomic and molecular approaches. Our whole genome analysis of the two groups identified differential SNPs between the CMS and non-CMS subjects in the ARID1B region. Under hypoxia, the expression levels of ARID1B significantly increased in the non-CMS cells but decreased in the CMS cells. At the molecular level, ARID1B knockdown (KD) in non-CMS cells increased the levels of the transcriptional regulator GATA1 by 3-fold and RBC levels by 100-fold under hypoxia. ARID1B KD in non-CMS cells led to increased proliferation and EPO sensitivity by lowering p53 levels and decreasing apoptosis through GATA1 mediation. Interestingly, under hypoxia ARID1B showed an epigenetic role, altering the chromatin states of erythroid genes. Indeed, combined Real-time PCR and ATAC-Seq results showed that ARID1B modulates the expression of GATA1 and p53 and chromatin accessibility at GATA1/p53 target genes. We conclude that ARID1B is a novel erythroid regulator under hypoxia that controls various aspects of erythropoiesis in high-altitude dwellers.
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Affiliation(s)
- Priti Azad
- Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Andrew B Caldwell
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | | | - Nathanael J Spann
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Ali Akbari
- Department of Genetics, Harvard Medical School, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Francisco C Villafuerte
- Laboratorio de Fisiología del Transporte de Oxigeno/Fisiología Comparada, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, 31, Peru
| | - Daniela Bermudez
- Laboratorio de Fisiología del Transporte de Oxigeno/Fisiología Comparada, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, 31, Peru
| | - Helen Zhao
- Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Orit Poulsen
- Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Dan Zhou
- Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Vineet Bafna
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Shankar Subramaniam
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.,Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.,Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.,Department of Nanoengineering, University of California, San Diego, La Jolla, CA, USA
| | - Gabriel G Haddad
- Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. .,Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. .,Rady Children's Hospital, San Diego, CA, 92123, USA.
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13
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Batie M, Frost J, Shakir D, Rocha S. Regulation of chromatin accessibility by hypoxia and HIF. Biochem J 2022; 479:767-786. [PMID: 35258521 PMCID: PMC9022986 DOI: 10.1042/bcj20220008] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 11/17/2022]
Abstract
Reduced oxygen availability (hypoxia) can act as a signalling cue in physiological processes such as development, but also in pathological conditions such as cancer or ischaemic disease. As such, understanding how cells and organisms respond to hypoxia is of great importance. The family of transcription factors called Hypoxia Inducible Factors (HIFs) co-ordinate a transcriptional programme required for survival and adaptation to hypoxia. However, the effects of HIF on chromatin accessibility are currently unclear. Here, using genome wide mapping of chromatin accessibility via ATAC-seq, we find hypoxia induces loci specific changes in chromatin accessibility are enriched at a subset hypoxia transcriptionally responsive genes, agreeing with previous data using other models. We show for the first time that hypoxia inducible changes in chromatin accessibility across the genome are predominantly HIF dependent, rapidly reversible upon reoxygenation and partially mimicked by HIF-α stabilisation independent of molecular dioxygenase inhibition. This work demonstrates that HIF is central to chromatin accessibility alterations in hypoxia, and has implications for our understanding of gene expression regulation by hypoxia and HIF.
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Affiliation(s)
- Michael Batie
- Department of Molecular Physiology and Cell Signalling, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, U.K
| | - Julianty Frost
- Department of Molecular Physiology and Cell Signalling, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, U.K
| | - Dilem Shakir
- Department of Molecular Physiology and Cell Signalling, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, U.K
| | - Sonia Rocha
- Department of Molecular Physiology and Cell Signalling, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, U.K
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14
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Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol 2021; 18:751-772. [PMID: 34326502 DOI: 10.1038/s41571-021-00539-4] [Citation(s) in RCA: 249] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.
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15
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Epigenetic Alterations in Pediatric Sleep Apnea. Int J Mol Sci 2021; 22:ijms22179523. [PMID: 34502428 PMCID: PMC8430725 DOI: 10.3390/ijms22179523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 12/03/2022] Open
Abstract
Pediatric obstructive sleep apnea has significant negative effects on health and behavior in childhood including depression, failure to thrive, neurocognitive impairment, and behavioral issues. It is strongly associated with an increased risk for chronic adult disease such as obesity and diabetes, accelerated atherosclerosis, and endothelial dysfunction. Accumulating evidence suggests that adult-onset non-communicable diseases may originate from early life through a process by which an insult applied at a critical developmental window causes long-term effects on the structure or function of an organism. In recent years, there has been increased interest in the role of epigenetic mechanisms in the pathogenesis of adult disease susceptibility. Epigenetic mechanisms that influence adaptive variability include histone modifications, non-coding RNAs, and DNA methylation. This review will highlight what is currently known about the phenotypic associations of epigenetic modifications in pediatric obstructive sleep apnea and will emphasize the importance of epigenetic changes as both modulators of chronic disease and potential therapeutic targets.
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16
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Weinhouse C. The roles of inducible chromatin and transcriptional memory in cellular defense system responses to redox-active pollutants. Free Radic Biol Med 2021; 170:85-108. [PMID: 33789123 PMCID: PMC8382302 DOI: 10.1016/j.freeradbiomed.2021.03.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/17/2022]
Abstract
People are exposed to wide range of redox-active environmental pollutants. Air pollution, heavy metals, pesticides, and endocrine disrupting chemicals can disrupt cellular redox status. Redox-active pollutants in our environment all trigger their own sets of specific cellular responses, but they also activate a common set of general stress responses that buffer the cell against homeostatic insults. These cellular defense system (CDS) pathways include the heat shock response, the oxidative stress response, the hypoxia response, the unfolded protein response, the DNA damage response, and the general stress response mediated by the stress-activated p38 mitogen-activated protein kinase. Over the past two decades, the field of environmental epigenetics has investigated epigenetic responses to environmental pollutants, including redox-active pollutants. Studies of these responses highlight the role of chromatin modifications in controlling the transcriptional response to pollutants and the role of transcriptional memory, often referred to as "epigenetic reprogramming", in predisposing previously exposed individuals to more potent transcriptional responses on secondary challenge. My central thesis in this review is that high dose or chronic exposure to redox-active pollutants leads to transcriptional memories at CDS target genes that influence the cell's ability to mount protective responses. To support this thesis, I will: (1) summarize the known chromatin features required for inducible gene activation; (2) review the known forms of transcriptional memory; (3) discuss the roles of inducible chromatin and transcriptional memory in CDS responses that are activated by redox-active environmental pollutants; and (4) propose a conceptual framework for CDS pathway responsiveness as a readout of total cellular exposure to redox-active pollutants.
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Affiliation(s)
- Caren Weinhouse
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, 97214, USA.
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17
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Telarovic I, Wenger RH, Pruschy M. Interfering with Tumor Hypoxia for Radiotherapy Optimization. J Exp Clin Cancer Res 2021; 40:197. [PMID: 34154610 PMCID: PMC8215813 DOI: 10.1186/s13046-021-02000-x] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/30/2021] [Indexed: 12/11/2022] Open
Abstract
Hypoxia in solid tumors is an important predictor of treatment resistance and poor clinical outcome. The significance of hypoxia in the development of resistance to radiotherapy has been recognized for decades and the search for hypoxia-targeting, radiosensitizing agents continues. This review summarizes the main hypoxia-related processes relevant for radiotherapy on the subcellular, cellular and tissue level and discusses the significance of hypoxia in radiation oncology, especially with regard to the current shift towards hypofractionated treatment regimens. Furthermore, we discuss the strategies to interfere with hypoxia for radiotherapy optimization, and we highlight novel insights into the molecular pathways involved in hypoxia that might be utilized to increase the efficacy of radiotherapy.
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Affiliation(s)
- Irma Telarovic
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
| | - Roland H Wenger
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland
| | - Martin Pruschy
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
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18
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PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation. Cells 2021; 10:cells10061425. [PMID: 34200988 PMCID: PMC8228889 DOI: 10.3390/cells10061425] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/27/2021] [Accepted: 06/04/2021] [Indexed: 11/16/2022] Open
Abstract
PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.
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19
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Vinaiphat A, Low JK, Yeoh KW, Chng WJ, Sze SK. Application of Advanced Mass Spectrometry-Based Proteomics to Study Hypoxia Driven Cancer Progression. Front Oncol 2021; 11:559822. [PMID: 33708620 PMCID: PMC7940826 DOI: 10.3389/fonc.2021.559822] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the largest contributors to the burden of chronic disease in the world and is the second leading cause of death globally. It is associated with episodes of low-oxygen stress (hypoxia or ischemia/reperfusion) that promotes cancer progression and therapeutic resistance. Efforts have been made in the past using traditional proteomic approaches to decipher oxygen deprivation stress-related mechanisms of the disease initiation and progression and to identify key proteins as a therapeutic target for the treatment and prevention. Despite the potential benefits of proteomic in translational research for the discovery of new drugs, the therapeutic outcome with this approach has not met expectations in clinical trials. This is mainly due to the disease complexity which possess a multifaceted molecular pathology. Therefore, novel strategies to identify and characterize clinically important sets of modulators and molecular events for multi-target drug discovery are needed. Here, we review important past and current studies on proteomics in cancer with an emphasis on recent pioneered labeling approaches in mass spectrometry (MS)-based systematic quantitative analysis to improve clinical success. We also discuss the results of the selected innovative publications that integrate advanced proteomic technologies (e.g. MALDI-MSI, pSILAC/SILAC/iTRAQ/TMT-LC-MS/MS, MRM-MS) for comprehensive analysis of proteome dynamics in different biosystems, including cell type, cell species, and subcellular proteome (i.e. secretome and chromatome). Finally, we discuss the future direction and challenges in the application of these technological advancements in mass spectrometry within the context of cancer and hypoxia.
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Affiliation(s)
- Arada Vinaiphat
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Jee Keem Low
- Department of Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Kheng Wei Yeoh
- Department of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Wee Joo Chng
- Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore
| | - Siu Kwan Sze
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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20
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Chopra A, Adhikary H, Willmore WG, Biggar KK. Insights into The Function and Regulation of Jumonji C Lysine Demethylases as Hypoxic Responsive Enzymes. Curr Protein Pept Sci 2021; 21:642-654. [PMID: 31889485 DOI: 10.2174/1389203721666191231104225] [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: 08/14/2019] [Revised: 10/14/2019] [Accepted: 10/22/2019] [Indexed: 12/30/2022]
Abstract
Cellular responses to hypoxia (low oxygen) are governed by oxygen sensitive signaling pathways. Such pathways, in part, are controlled by enzymes with oxygen-dependent catalytic activity, of which the role of prolyl 4-hydroxylases has been widely reviewed. These enzymes inhibit hypoxic response by inducing the oxygen-dependent degradation of hypoxia-inducible factor 1α, the master regulator of the transcriptional hypoxic response. Jumonji C domain-containing lysine demethylases are similar enzymes which share the same oxygen-dependent catalytic mechanism as prolyl 4- hydroxylases. Traditionally, the role of lysine demethylases has been studied in relation to demethylation activity against histone substrates, however, within the past decade an increasing number of nonhistone protein targets have been revealed, some of which have a key role in survival in the hypoxic tumor microenvironment. Within this review, we highlight the involvement of methyllysine in the hypoxic response with a focus on the HIF signaling pathway, the regulation of demethylase activity by oxygen, and provide insights into notable areas of future hypoxic demethylase research.
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Affiliation(s)
- Anand Chopra
- Department of Biology, Carleton University, 1125 Colonel By Dr, Ottawa, ON, K1S 5B6, Canada
| | - Hemanta Adhikary
- Department of Biology, Carleton University, 1125 Colonel By Dr, Ottawa, ON, K1S 5B6, Canada
| | - William G Willmore
- Department of Biology, Carleton University, 1125 Colonel By Dr, Ottawa, ON, K1S 5B6, Canada
| | - Kyle K Biggar
- Department of Biology, Carleton University, 1125 Colonel By Dr, Ottawa, ON, K1S 5B6, Canada
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21
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Macedo-Silva C, Miranda-Gonçalves V, Lameirinhas A, Lencart J, Pereira A, Lobo J, Guimarães R, Martins AT, Henrique R, Bravo I, Jerónimo C. JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma. Cell Death Dis 2020; 11:1068. [PMID: 33318475 PMCID: PMC7736883 DOI: 10.1038/s41419-020-03279-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients' survival.
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Affiliation(s)
- Catarina Macedo-Silva
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
| | - Vera Miranda-Gonçalves
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
| | - Ana Lameirinhas
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
| | - Joana Lencart
- Medical Physics, Radiobiology and Radiation Protection Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
- Departments of Medical Physics, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Alexandre Pereira
- Medical Physics, Radiobiology and Radiation Protection Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
- Departments of Medical Physics, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - João Lobo
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
- Departments of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar - University of Porto (ICBAS-UP), Porto, Portugal
| | - Rita Guimarães
- Departments of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Ana Teresa Martins
- Departments of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Rui Henrique
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
- Departments of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar - University of Porto (ICBAS-UP), Porto, Portugal
| | - Isabel Bravo
- Medical Physics, Radiobiology and Radiation Protection Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar - University of Porto (ICBAS-UP), Porto, Portugal.
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22
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Abstract
2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.
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Affiliation(s)
- Julie-Aurore Losman
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Peppi Koivunen
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
| | - William G Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA.
- Howard Hughes Medical Institute (HHMI), Chevy Chase, MD, USA.
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23
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Liu OHF, Kiema M, Beter M, Ylä-Herttuala S, Laakkonen JP, Kaikkonen MU. Hypoxia-Mediated Regulation of Histone Demethylases Affects Angiogenesis-Associated Functions in Endothelial Cells. Arterioscler Thromb Vasc Biol 2020; 40:2665-2677. [PMID: 32938217 DOI: 10.1161/atvbaha.120.315214] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Previous studies have demonstrated that the expression of several lysine (K)-specific demethylases (KDMs) is induced by hypoxia. Here, we sought to investigate the exact mechanisms underlying this regulation and its functional implications for endothelial cell function, such as angiogenesis. Approach and Results: We analyzed the expression changes of KDMs under hypoxia and modulation of HIF (hypoxia-inducible factor) expression using GRO-Seq and RNA-Seq in endothelial cells. We provide evidence that the majority of the KDMs are induced at the level of nascent transcription mediated by the action of HIF-1α and HIF-2α. Importantly, we show that transcriptional changes at the level of initiation represent the major mechanism of gene activation. To delineate the epigenetic effects of hypoxia and HIF activation in normoxia, we analyzed the genome-wide changes of H3K27me3 using chromosome immunoprecipitation-Seq. We discovered a redistribution of H3K27me3 at ≈2000 to 3000 transcriptionally active loci nearby genes implicated in angiogenesis. Among these, we demonstrate that vascular endothelial growth factor A (VEGFA) expression is partly induced by KDM4B- and KDM6B-mediated demethylation of nearby regions. Knockdown of KDM4B and KDM6B decreased cell proliferation, tube formation, and endothelial sprouting while affecting hundreds of genes associated with angiogenesis. These findings provide novel insights into the regulation of KDMs by hypoxia and the epigenetic regulation of VEGFA-mediated angiogenesis. CONCLUSIONS Our study describes an additional level of epigenetic regulation where hypoxia induces redistribution of H3K27me3 around genes implicated in proliferation and angiogenesis. More specifically, we demonstrate that KDM4B and KDM6B play a key role in modulating the expression of the major angiogenic driver VEGFA.
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Affiliation(s)
- Oscar Hsin-Fu Liu
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio (O.H.-F.L., M.K., M.B., S.Y.-H., J.P.L., M.U.K.)
| | - Miika Kiema
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio (O.H.-F.L., M.K., M.B., S.Y.-H., J.P.L., M.U.K.)
| | - Mustafa Beter
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio (O.H.-F.L., M.K., M.B., S.Y.-H., J.P.L., M.U.K.)
| | - Seppo Ylä-Herttuala
- Science Service Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.)
| | - Johanna P Laakkonen
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio (O.H.-F.L., M.K., M.B., S.Y.-H., J.P.L., M.U.K.)
| | - Minna U Kaikkonen
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio (O.H.-F.L., M.K., M.B., S.Y.-H., J.P.L., M.U.K.)
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24
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Begg K, Tavassoli M. Inside the hypoxic tumour: reprogramming of the DDR and radioresistance. Cell Death Discov 2020; 6:77. [PMID: 32864165 PMCID: PMC7434912 DOI: 10.1038/s41420-020-00311-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 12/19/2022] Open
Abstract
The hypoxic tumour is a chaotic landscape of struggle and adaption. Against the adversity of oxygen starvation, hypoxic cancer cells initiate a reprogramming of transcriptional activities, allowing for survival, metastasis and treatment failure. This makes hypoxia a crucial feature of aggressive tumours. Its importance, to cancer and other diseases, was recognised by the award of the 2019 Nobel Prize in Physiology or Medicine for research contributing to our understanding of the cellular response to oxygen deprivation. For cancers with limited treatment options, for example those that rely heavily on radiotherapy, the results of hypoxic adaption are particularly restrictive to treatment success. A fundamental aspect of this hypoxic reprogramming with direct relevance to radioresistance, is the alteration to the DNA damage response, a complex set of intermingling processes that guide the cell (for good or for bad) towards DNA repair or cell death. These alterations, compounded by the fact that oxygen is required to induce damage to DNA during radiotherapy, means that hypoxia represents a persistent obstacle in the treatment of many solid tumours. Considerable research has been done to reverse, correct or diminish hypoxia's power over successful treatment. Though many clinical trials have been performed or are ongoing, particularly in the context of imaging studies and biomarker discovery, this research has yet to inform clinical practice. Indeed, the only hypoxia intervention incorporated into standard of care is the use of the hypoxia-activated prodrug Nimorazole, for head and neck cancer patients in Denmark. Decades of research have allowed us to build a picture of the shift in the DNA repair capabilities of hypoxic cancer cells. A literature consensus tells us that key signal transducers of this response are upregulated, where repair proteins are downregulated. However, a complete understanding of how these alterations lead to radioresistance is yet to come.
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Affiliation(s)
- Katheryn Begg
- Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King’s College London, Hodgkin Building, London, SE1 1UL UK
| | - Mahvash Tavassoli
- Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King’s College London, Hodgkin Building, London, SE1 1UL UK
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25
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Kamei H. Oxygen and embryonic growth: the role of insulin-like growth factor signaling. Gen Comp Endocrinol 2020; 294:113473. [PMID: 32247621 DOI: 10.1016/j.ygcen.2020.113473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/05/2020] [Accepted: 03/28/2020] [Indexed: 01/03/2023]
Abstract
Oxygen is indispensable for the efficient release of chemical energy from nutrient molecules in cells. Therefore, the local oxygen tension is one of the most critical factors affecting physiological processes. In most viviparous species, many pathological conditions result in abnormal oxygen tension in the uterus, which modifies the growth and development of the fetus. Insulin-like growth factor (IGF/Igf) is one of the most important hormones for the regulation of somatic growth in animals. Changes in oxygen levels modulate the activity of the IGF/Igf signaling system, which in turn regulates the embryonic growth rate. In general, there are serious difficulties associated with monitoring and studying rodent embryos in utero. The zebrafish is a convenient experimental model to study the relationship between embryonic growth and environmental conditions. Most importantly, the fish model makes it possible to rapidly evaluate embryonic growth and development under entirely controlled environments without interfering with the mother organism. In this review, firstly an overview is given of the fluctuation of environmental oxygen, the IGF-system, and the advantages of the zebrafish model for studying embryonic growth. Then, the relationships of dynamic environmental oxygen and embryonic growth rate are outlined with a specific focus on the changes in the IGF/Igf-system in the zebrafish model. This review will shed light on the fine-tuning mechanisms of the embryonic IGF/Igf-system under different oxygen levels, including constant normoxia, hypoxia, and re-oxygenation.
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Affiliation(s)
- Hiroyasu Kamei
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, 11-4-1, Ossaka, Noto, Ishikawa 927-0552, Japan.
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26
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Hammarlund EU. Harnessing hypoxia as an evolutionary driver of complex multicellularity. Interface Focus 2020; 10:20190101. [PMID: 32642048 DOI: 10.1098/rsfs.2019.0101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2020] [Indexed: 12/11/2022] Open
Abstract
Animal tissue requires low-oxygen conditions for its maintenance. The need for low-oxygen conditions contrasts with the idea of an evolutionary leap in animal diversity as a result of expanding oxic conditions. To accommodate tissue renewal at oxic conditions, however, vertebrate animals and vascular plants demonstrate abilities to access hypoxia. Here, I argue that multicellular organisms sustain oxic conditions first after internalizing hypoxic conditions. The 'harnessing' of hypoxia has allowed multicellular evolution to leave niches that were stable in terms of oxygen concentrations for those where oxygen fluctuates. Since oxygen fluctuates in most settings on Earth's surface, the ancestral niche would have been a deep marine setting. The hypothesis that 'large life' depends on harnessing hypoxia is illustrated in the context of conditions that promote the immature cell phenotype (stemness) in animal physiology and tumour biology and offers one explanation for the general rarity of diverse multicellularity over most of Earth's history.
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Affiliation(s)
- Emma U Hammarlund
- Department of Laboratory Medicine, Translational Cancer Research, Lund University, Scheelevägen 2, Medicon Village Building 404, 223 81 Lund, Sweden.,Department of Geology, Lund University, Sölvegatan 12, 223 62 Lund, Sweden
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27
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Green HLH, Brewer AC. Dysregulation of 2-oxoglutarate-dependent dioxygenases by hyperglycaemia: does this link diabetes and vascular disease? Clin Epigenetics 2020; 12:59. [PMID: 32345373 PMCID: PMC7189706 DOI: 10.1186/s13148-020-00848-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
The clinical, social and economic burden of cardiovascular disease (CVD) associated with diabetes underscores an urgency for understanding the disease aetiology. Evidence suggests that the hyperglycaemia associated with diabetes is, of itself, causal in the development of endothelial dysfunction (ED) which is recognised to be the critical determinant in the development of CVD. It is further recognised that epigenetic modifications associated with changes in gene expression are causal in both the initiation of ED and the progression to CVD. Understanding whether and how hyperglycaemia induces epigenetic modifications therefore seems crucial in the development of preventative treatments. A mechanistic link between energy metabolism and epigenetic regulation is increasingly becoming explored as key energy metabolites typically serve as substrates or co-factors for epigenetic modifying enzymes. Intriguing examples are the ten-eleven translocation and Jumonji C proteins which facilitate the demethylation of DNA and histones respectively. These are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require the tricarboxylic acid metabolite, α-ketoglutarate and molecular oxygen (O2) as substrates and Fe (II) as a co-factor. An understanding of precisely how the biochemical effects of high glucose exposure impact upon cellular metabolism, O2 availability and cellular redox in endothelial cells (ECs) may therefore elucidate (in part) the mechanistic link between hyperglycaemia and epigenetic modifications causal in ED and CVD. It would also provide significant proof of concept that dysregulation of the epigenetic landscape may be causal rather than consequential in the development of pathology.
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Affiliation(s)
- Hannah L H Green
- School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre of Research Excellence, London, UK
| | - Alison C Brewer
- School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre of Research Excellence, London, UK.
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28
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Geng H, Hao L, Cheng Y, Wang C, Huang S, Wei W, Yang R, Li H, Liu S, Yu H, Lu H. Interaction between CA repeat microsatellites and HIF1α regulated the transcriptional activity of porcine IGF1 promoter. J Appl Genet 2020; 61:105-112. [PMID: 31673965 DOI: 10.1007/s13353-019-00529-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 09/08/2019] [Accepted: 10/18/2019] [Indexed: 02/03/2023]
Abstract
Insulin-like growth factor 1 (IGF1) is pivotal in the regulation of animal growth. Highly polymorphic CA repeat microsatellites have been identified in the IGF1 promoter region of different breeds of pigs. Previous studies showed that CA repeat microsatellites are associated with circulating IGF1 level. However, the mechanisms by which CA repeat microsatellites regulate IGF1 expression remain unclear. This study aimed to detect the association of CA repeat microsatellites with the transcriptional regulation of porcine IGF1 and the possible mechanisms. Results revealed that the number of CA repeats in porcine IGF1 promoter was 14-18, and a promoter with 14 or 15 CA repeats had a higher transcriptional activity (P < 0.01). Transcription factor hypoxia-inducible factor 1 subunit alpha (HIF1α) was confirmed to bind to the binding site upstream of CA repeat microsatellites. The microsatellites with 14 or 15 CA repeats were more sensitive to changes in the HIF1α expression level (P < 0.01). These results suggested that CA repeat microsatellites and HIF1α affected the transcriptional activity of each other in the regulation of IGF1 expression, thereby implying an interaction between them. Overall, this study provided novel evidence for elucidating the effects of CA repeat microsatellites on the transcriptional regulation of porcine IGF1.
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Affiliation(s)
- Hongwei Geng
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Linlin Hao
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Yunyun Cheng
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Chunli Wang
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Shan Huang
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Wenzhen Wei
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Rui Yang
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Haoyang Li
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Songcai Liu
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
- Five-Star Animal Health Pharmaceutical Factory of Jilin Province, Changchun, Jilin, 130062, China.
| | - Hao Yu
- College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
| | - Huayi Lu
- The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041, China.
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29
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Lal S, Comer JM, Konduri PC, Shah A, Wang T, Lewis A, Shoffner G, Guo F, Zhang L. Heme promotes transcriptional and demethylase activities of Gis1, a member of the histone demethylase JMJD2/KDM4 family. Nucleic Acids Res 2019; 46:215-228. [PMID: 29126261 PMCID: PMC5758875 DOI: 10.1093/nar/gkx1051] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 10/19/2017] [Indexed: 12/17/2022] Open
Abstract
The yeast Gis1 protein is a transcriptional regulator belonging to the JMJD2/KDM4 subfamily of demethylases that contain a JmjC domain, which are highly conserved from yeast to humans. They have important functions in histone methylation, cellular signaling and tumorigenesis. Besides serving as a cofactor in many proteins, heme is known to directly regulate the activities of proteins ranging from transcriptional regulators to potassium channels. Here, we report a novel mechanism governing heme regulation of Gis1 transcriptional and histone demethylase activities. We found that two Gis1 modules, the JmjN + JmjC domain and the zinc finger (ZnF), can bind to heme specifically in vitro. In vivo functional analysis showed that the ZnF, not the JmjN + JmjC domain, promotes heme activation of transcriptional activity. Likewise, measurements of the demethylase activity of purified Gis1 proteins showed that full-length Gis1 and the JmjN + JmjC domain both possess demethylase activity. However, heme potentiates the demethylase activity of full-length Gis1, but not that of the JmjN + JmjC domain, which can confer heme activation of transcriptional activity in an unrelated protein. These results demonstrate that Gis1 represents a novel class of multi-functional heme sensing and signaling proteins, and that heme binding to the ZnF stimulates Gis1 demethylase and transcriptional activities.
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Affiliation(s)
- Sneha Lal
- Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
| | - Jonathan M Comer
- Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
| | - Purna C Konduri
- Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
| | - Ajit Shah
- Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Tianyuan Wang
- Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
| | - Anthony Lewis
- Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
| | - Grant Shoffner
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Feng Guo
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Li Zhang
- Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
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30
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Kifune T, Ito H, Ishiyama M, Iwasa S, Takei H, Hasegawa T, Asano M, Shirakawa T. Hypoxia-induced upregulation of angiogenic factors in immortalized human periodontal ligament fibroblasts. J Oral Sci 2019; 60:519-525. [PMID: 30587686 DOI: 10.2334/josnusd.17-0441] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Hypoxia induces complex cellular responses that are mediated by a key transcription factor, hypoxia-inducible factor-1 (HIF-1). HIF-1 promotes production of cytokines and angiogenic factors and contributes to recovery of injured tissues. In the present study, expressions of angiogenin (ANG) and vascular endothelial growth factor (VEGF), which are potent angiogenic factors in mammalian tissues, were examined in immortalized fibroblasts exposed to hypoxia. After 24 h of exposure to hypoxia, ANG and VEGF mRNAs expressions were significantly elevated in periodontal ligament (PDL) fibroblasts but not in embryonic fibroblasts. Hypoxia also increased productions of ANG and VEGF proteins in PDL fibroblasts. HIF-1α mRNA expression was not affected by hypoxia in either fibroblast, although HIF-1α protein expression was enhanced after exposure to hypoxia. Treatment of PDL fibroblasts with dimethyloxaloylglycine, a prolyl hydroxylase inhibitor that stabilizes the HIF-1α protein, significantly increased expressions of ANG and VEGF mRNAs under normoxia. This suggests that stabilization of HIF-1α is crucial for upregulation of ANG and VEGF in PDL fibroblasts. These results indicate that, under hypoxic conditions, HIF-1α upregulates synthesis of ANG and VEGF in PDL fibroblasts and promotes angiogenesis.
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Affiliation(s)
- Takashi Kifune
- Department of Pediatric Dentistry, Nihon University School of Dentistry
| | - Hisanori Ito
- Department of Pediatric Dentistry, Nihon University School of Dentistry
| | - Misa Ishiyama
- Department of Pediatric Dentistry, Nihon University School of Dentistry
| | - Satoko Iwasa
- Department of Pediatric Dentistry, Nihon University School of Dentistry
| | - Hiroki Takei
- Department of Pediatric Dentistry, Nihon University School of Dentistry
| | | | - Masatake Asano
- Department of Pathology, Nihon University School of Dentistry
| | - Tetsuo Shirakawa
- Department of Pediatric Dentistry, Nihon University School of Dentistry.,Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry
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31
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Abstract
Hypoxia signals directly to chromatin via histone demethylases to alter gene expression
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Affiliation(s)
- Paolo Gallipoli
- Wellcome Trust-MRC Cambridge Stem Cell Institute; Department of Haematology, University of Cambridge; and Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Brian J P Huntly
- Wellcome Trust-MRC Cambridge Stem Cell Institute; Department of Haematology, University of Cambridge; and Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
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32
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Chakraborty AA, Laukka T, Myllykoski M, Ringel AE, Booker MA, Tolstorukov MY, Meng YJ, Meier SR, Jennings RB, Creech AL, Herbert ZT, McBrayer SK, Olenchock BA, Jaffe JD, Haigis MC, Beroukhim R, Signoretti S, Koivunen P, Kaelin WG. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 2019; 363:1217-1222. [PMID: 30872525 DOI: 10.1126/science.aaw1026] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 01/15/2019] [Indexed: 12/13/2022]
Abstract
Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG-independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.
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Affiliation(s)
- Abhishek A Chakraborty
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Tuomas Laukka
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland
| | - Matti Myllykoski
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland
| | - Alison E Ringel
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Matthew A Booker
- Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Michael Y Tolstorukov
- Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yuzhong Jeff Meng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.,Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.,Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.,Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.,The Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA
| | - Samuel R Meier
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Rebecca B Jennings
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Amanda L Creech
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Zachary T Herbert
- Molecular Biology Core Facility, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Samuel K McBrayer
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Benjamin A Olenchock
- Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Jacob D Jaffe
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Marcia C Haigis
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Rameen Beroukhim
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.,Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.,Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Peppi Koivunen
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
| | - William G Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. .,Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
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33
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Batie M, Frost J, Frost M, Wilson JW, Schofield P, Rocha S. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 2019; 363:1222-1226. [DOI: 10.1126/science.aau5870] [Citation(s) in RCA: 177] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 11/05/2018] [Accepted: 01/24/2019] [Indexed: 12/22/2022]
Abstract
Oxygen is essential for the life of most multicellular organisms. Cells possess enzymes called molecular dioxygenases that depend on oxygen for activity. A subclass of molecular dioxygenases is the histone demethylase enzymes, which are characterized by the presence of a Jumanji-C (JmjC) domain. Hypoxia can alter chromatin, but whether this is a direct effect on JmjC-histone demethylases or due to other mechanisms is unknown. Here, we report that hypoxia induces a rapid and hypoxia-inducible factor–independent induction of histone methylation in a range of human cultured cells. Genomic locations of histone-3 lysine-4 trimethylation (H3K4me3) and H3K36me3 after a brief exposure of cultured cells to hypoxia predict the cell’s transcriptional response several hours later. We show that inactivation of one of the JmjC-containing enzymes, lysine demethylase 5A (KDM5A), mimics hypoxia-induced cellular responses. These results demonstrate that oxygen sensing by chromatin occurs via JmjC-histone demethylase inhibition.
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34
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35
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Lamadema N, Burr S, Brewer AC. Dynamic regulation of epigenetic demethylation by oxygen availability and cellular redox. Free Radic Biol Med 2019; 131:282-298. [PMID: 30572012 DOI: 10.1016/j.freeradbiomed.2018.12.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 12/04/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023]
Abstract
The chromatin structure of the mammalian genome must facilitate both precisely-controlled DNA replication together with tightly-regulated gene transcription. This necessarily involves complex mechanisms and processes which remain poorly understood. It has long been recognised that the epigenetic landscape becomes established during embryonic development and acts to specify and determine cell fate. In addition, the chromatin structure is highly dynamic and allows for both cellular reprogramming and homeostatic modulation of cell function. In this respect, the functions of epigenetic "erasers", which act to remove covalently-linked epigenetic modifications from DNA and histones are critical. The enzymatic activities of the TET and JmjC protein families have been identified as demethylases which act to remove methyl groups from DNA and histones, respectively. Further, they are characterised as members of the Fe(II)- and 2-oxoglutarate-dependent dioxygenase superfamily. This provides the intriguing possibility that their enzymatic activities may be modulated by cellular metabolism, oxygen availability and redox-based mechanisms, all of which are likely to display dynamic cell- and tissue-specific patterns of flux. Here we discuss the current evidence for such [O2]- and redox-dependent regulation of the TET and Jmjc demethylases and the potential physiological and pathophysiological functional consequences of such regulation.
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Affiliation(s)
- Nermina Lamadema
- School of Cardiovascular Medicine & Sciences, King's College London BHF Centre of Research Excellence, United Kingdom
| | - Simon Burr
- School of Cardiovascular Medicine & Sciences, King's College London BHF Centre of Research Excellence, United Kingdom
| | - Alison C Brewer
- School of Cardiovascular Medicine & Sciences, King's College London BHF Centre of Research Excellence, United Kingdom.
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36
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Nalivaeva NN, Turner AJ, Zhuravin IA. Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration. Front Neurosci 2018; 12:825. [PMID: 30510498 PMCID: PMC6254649 DOI: 10.3389/fnins.2018.00825] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/22/2018] [Indexed: 12/15/2022] Open
Abstract
This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.
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Affiliation(s)
- Natalia N. Nalivaeva
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
- Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
| | - Anthony J. Turner
- Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
| | - Igor A. Zhuravin
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
- Research Centre, Saint-Petersburg State Pediatric Medical University, St. Petersburg, Russia
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37
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Vetrovoy OV, Glushchenko TS, Sarieva KV, Tyulkova EI, Aramisova RM, Samoilov MO. The Acetylation of Histone H3 at Lys24 Is Accompanied by Delayed Expression of Neuroprotective Proteins Bcl-2 and BDNF in the Neocortex of Rats Exposed to Severe Hypoxia: the Effect of Postconditioning. NEUROCHEM J+ 2018. [DOI: 10.1134/s1819712418030157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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38
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Yu X, Ma R, Wu Y, Zhai Y, Li S. Reciprocal Regulation of Metabolic Reprogramming and Epigenetic Modifications in Cancer. Front Genet 2018; 9:394. [PMID: 30283496 PMCID: PMC6156463 DOI: 10.3389/fgene.2018.00394] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 08/29/2018] [Indexed: 11/13/2022] Open
Abstract
Cancer cells reprogram their metabolism to meet their demands for survival and proliferation. The metabolic plasticity of tumor cells help them adjust to changes in the availability and utilization of nutrients in the microenvironment. Recent studies revealed that many metabolites and metabolic enzymes have non-metabolic functions contributing to tumorigenesis. One major function is regulating epigenetic modifications to facilitate appropriate responses to environmental cues. Accumulating evidence showed that epigenetic modifications could in turn alter metabolism in tumors. Although a comprehensive understanding of the reciprocal connection between metabolic and epigenetic rewiring in cancer is lacking, some conceptual advances have been made. Understanding the link between metabolism and epigenetic modifications in cancer cells will shed lights on the development of more effective cancer therapies.
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Affiliation(s)
- Xilan Yu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China
| | - Rui Ma
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China
| | - Yinsheng Wu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China
| | - Yansheng Zhai
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China
| | - Shanshan Li
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China
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39
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Rubio-Cabetas MJ, Pons C, Bielsa B, Amador ML, Marti C, Granell A. Preformed and induced mechanisms underlies the differential responses of Prunus rootstock to hypoxia. JOURNAL OF PLANT PHYSIOLOGY 2018; 228:134-149. [PMID: 29913428 DOI: 10.1016/j.jplph.2018.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/01/2018] [Accepted: 06/06/2018] [Indexed: 06/08/2023]
Abstract
Analysis of the transcriptomic changes produced in response to hypoxia in root tissues from two rootstock Prunus genotypes differing in their sensitivity to waterlogging: resistant Myrobalan 'P.2175' (P. cerasifera Erhr.), and sensitive 'Felinem' hybrid [P. amygdalus Batsch × P. persica (L.) Batsch] revealed alterations in both metabolism and regulatory processes. Early hypoxia response in both genotypes is characterized by a molecular program aimed to adapt the cell metabolism to the new conditions. Upon hypoxia conditions, tolerant Myrobalan represses first secondary metabolism gene expression as a strategy to prevent the waste of resources/energy, and by the up-regulation of protein degradation genes probably leading to structural adaptations to long-term response to hypoxia. In response to the same conditions, sensitive 'Felinem' up-regulates a core of signal transduction and transcription factor genes. A combination of PLS-DA and qRT-PCR approaches revealed a set of transcription factors and signalling molecules as differentially regulated in the sensitive and tolerant genotypes including the peach orthologs for oxygen sensors. Apart from providing insights into the molecular processes underlying the differential response to waterlogging of two Prunus rootstocks, our approach reveals a set of candidate genes to be used expression biomarkers for biotech or breeding approaches to waterlogging tolerance.
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Affiliation(s)
- María J Rubio-Cabetas
- Hortofruticulture Department, Agrifood Research and Technology Centre of Aragon (CITA), Av. Montañana 930, 50059, Zaragoza, Spain
| | - Clara Pons
- Department of Fruit Quality and Biotechnology, Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC), Ingeniero Fausto Elio, s/n 46022 Valencia, Spain
| | - Beatriz Bielsa
- Hortofruticulture Department, Agrifood Research and Technology Centre of Aragon (CITA), Av. Montañana 930, 50059, Zaragoza, Spain
| | - María L Amador
- Hortofruticulture Department, Agrifood Research and Technology Centre of Aragon (CITA), Av. Montañana 930, 50059, Zaragoza, Spain
| | - Cristina Marti
- Department of Fruit Quality and Biotechnology, Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC), Ingeniero Fausto Elio, s/n 46022 Valencia, Spain
| | - Antonio Granell
- Department of Fruit Quality and Biotechnology, Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC), Ingeniero Fausto Elio, s/n 46022 Valencia, Spain.
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40
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Abdou AG, Farag AGA, Hammam M, Taie DM, Abdelaziz RA. Immunohistochemical expression HIF1α in chronic plaque psoriasis, an association with angiogenesis and proliferation. J Immunoassay Immunochem 2018; 39:249-262. [PMID: 29771632 DOI: 10.1080/15321819.2018.1472605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Psoriasis is characterized by excessive cell proliferation, angiogenesis, and regions of hypoxia. Hypoxia stimulates production of hypoxia inducible factors (HIFs) such as HIF1α. The aim of the present study is to investigate the possible role of HIF1α in pathogenesis of psoriasis and to correlate its expression with angiogenesis and proliferation in involved and uninvolved skin in patients with plaque psoriasis using CD34 and Ki-67. The current study was performed on 40 skin specimens of patients presented with chronic plaque psoriasis both involved and uninvolved together with 40 specimens from age- and sex-matched healthy volunteers as a control group. The specimens were submitted for HIF1α, CD34, and Ki-67 immunostaining. HIF1α was expressed in 37.5% of normal skin with mild intensity and cytoplasmic localization instead of its expression in 72.5% and 100% of uninvolved and involved psoriatic skin, respectively. Nucleocytoplasmic pattern of HIF1α was seen in 34.5% and 37.5% of uninvolved and involved psoriatic skin, respectively. Positive and intense expression of HIF1α as well as its nucleocytoplasmic localization were significantly in favor of psoriatic skin either involved or uninvolved in comparison to normal skin (P < 0.05). Intense HIF1α was significantly associated with microvessel density in both involved and uninvolved skin (P < 0.05). Nucleocytoplasmic pattern was significantly associated with epidermal acanthosis (P < 0.05) and tended to be associated with percentage of Ki-67 of psoriatic skin (P = 0.06). The present study demonstrated that HIF1α is upregulated in the skin of psoriatic cases (involved and uninvolved) compared to normal skin indicating its role in pathogenesis of psoriasis especially its active nuclear form that showed an association with angiogenesis and proliferation.
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Affiliation(s)
- Asmaa Gaber Abdou
- a Pathology Departments, Faculty of Medicine , Menoufia University , Shebein Elkom , Egypt
| | - Azza G A Farag
- b Dermatology Departments, Faculty of Medicine , Menoufia University , Shebein Elkom , Egypt
| | - Moustafa Hammam
- b Dermatology Departments, Faculty of Medicine , Menoufia University , Shebein Elkom , Egypt
| | - Doha Maher Taie
- a Pathology Departments, Faculty of Medicine , Menoufia University , Shebein Elkom , Egypt.,c Liver Institute, Menoufia University , Shebein Elkom , Egypt
| | - Reem Ahmed Abdelaziz
- b Dermatology Departments, Faculty of Medicine , Menoufia University , Shebein Elkom , Egypt
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41
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Jhelum P, Karisetty BC, Kumar A, Chakravarty S. Implications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models. Curr Neuropharmacol 2018; 15:815-830. [PMID: 27964703 PMCID: PMC5652028 DOI: 10.2174/1570159x14666161213143907] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 11/07/2016] [Accepted: 12/09/2016] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Understanding the complexities associated with the ischemic condition and identifying therapeutic targets in ischemia is a continued challenge in stroke biology. Emerging evidence reveals the potential involvement of epigenetic mechanisms in the incident and outcome of stroke, suggesting novel therapeutic options of targeting different molecules related to epigenetic regulation. OBJECTIVE This review summarizes our current understanding of ischemic pathophysiology, describes various in vivo and in vitro models of ischemia, and examines epigenetic modifications associated with the ischemic condition. METHOD We focus on microRNAs, DNA methylation, and histone modifying enzymes, and present how epigenetic studies are revealing novel drug target candidates in stroke. CONCLUSION Finally, we discuss emerging approaches for the prevention and treatment of stroke and post-stroke effects using pharmacological interventions with a wide therapeutic window.
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Affiliation(s)
- Priya Jhelum
- Chemical Biology, CSIR, Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India
| | - Bhanu C Karisetty
- Chemical Biology, CSIR, Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India
| | - Arvind Kumar
- CSIR, Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500007, India
| | - Sumana Chakravarty
- Chemical Biology, CSIR-Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad-500007, India
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42
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Batie M, Del Peso L, Rocha S. Hypoxia and Chromatin: A Focus on Transcriptional Repression Mechanisms. Biomedicines 2018; 6:biomedicines6020047. [PMID: 29690561 PMCID: PMC6027312 DOI: 10.3390/biomedicines6020047] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/26/2018] [Accepted: 04/19/2018] [Indexed: 12/20/2022] Open
Abstract
Hypoxia or reduced oxygen availability has been studied extensively for its ability to activate specific genes. Hypoxia-induced gene expression is mediated by the HIF transcription factors, but not exclusively so. Despite the extensive knowledge about how hypoxia activates genes, much less is known about how hypoxia promotes gene repression. In this review, we discuss the potential mechanisms underlying hypoxia-induced transcriptional repression responses. We highlight HIF-dependent and independent mechanisms as well as the potential roles of dioxygenases with functions at the nucleosome and DNA level. Lastly, we discuss recent evidence regarding the involvement of transcriptional repressor complexes in hypoxia.
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Affiliation(s)
- Michael Batie
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, UK.
| | - Luis Del Peso
- Department of Biochemistry, Institute of Biomedical Research, Autonomous Madrid University, Arturo Duperier, 4. 28029 Madrid, Spain.
| | - Sonia Rocha
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, UK.
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43
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Robinson CM, Lefebvre F, Poon BP, Bousard A, Fan X, Lathrop M, Tost J, Kim WY, Riazalhosseini Y, Ohh M. Consequences of VHL Loss on Global DNA Methylome. Sci Rep 2018; 8:3313. [PMID: 29463811 PMCID: PMC5820357 DOI: 10.1038/s41598-018-21524-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 02/06/2018] [Indexed: 12/13/2022] Open
Abstract
In clear-cell renal cell carcinoma (ccRCC), loss of von Hippel-Lindau (VHL) tumour suppressor gene and reduced oxygen tension promote stabilisation of hypoxia-inducible factor (HIF) family of transcription factors, which promote changes in the expression of genes that contribute to oncogenesis. Multiple studies have demonstrated significant perturbations in DNA methylation in ccRCC via largely unclear mechanisms that modify the transcriptional output of tumour cells. Here, we show that the methylation status of the CpG dinucleotide within the consensus hypoxia-responsive element (HRE) markedly influences the binding of HIF and that the loss of VHL results in significant alterations in the DNA methylome. Surprisingly, hypoxia, which likewise promotes HIF stabilisation and activation, has relatively few effects on global DNA methylation. Gene expression analysis of ccRCC patient samples highlighted expression of a group of genes whose transcription correlated with methylation changes, including hypoxic responsive genes such as VEGF and TGF. These results suggest that the loss of VHL alters DNA methylation profile across the genome, commonly associated with and contributing to ccRCC progression.
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Affiliation(s)
- Claire M Robinson
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada
| | - Francois Lefebvre
- Canadian Centre for Computational Genomics (C3G), 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Betty P Poon
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada
| | - Aurelie Bousard
- Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, 2 rue Gaston Crémieux, 91000, Evry, France
| | - Xiaojun Fan
- Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.,McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Mark Lathrop
- Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.,McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Jorg Tost
- Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, 2 rue Gaston Crémieux, 91000, Evry, France
| | - William Y Kim
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, North Carolina, USA
| | - Yasser Riazalhosseini
- Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.,McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Michael Ohh
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada. .,Department of Biochemistry, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada.
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44
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Burr S, Caldwell A, Chong M, Beretta M, Metcalf S, Hancock M, Arno M, Balu S, Kropf VL, Mistry RK, Shah AM, Mann GE, Brewer AC. Oxygen gradients can determine epigenetic asymmetry and cellular differentiation via differential regulation of Tet activity in embryonic stem cells. Nucleic Acids Res 2018; 46:1210-1226. [PMID: 29186571 PMCID: PMC5814828 DOI: 10.1093/nar/gkx1197] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 11/13/2017] [Accepted: 11/16/2017] [Indexed: 02/06/2023] Open
Abstract
Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis.
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Affiliation(s)
- Simon Burr
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Anna Caldwell
- King's Centre of Excellence for Mass Spectrometry, King's College London, London SE1 9NH, UK
| | - Mei Chong
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Matteo Beretta
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Stephen Metcalf
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Matthew Hancock
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Matthew Arno
- King's Genomic Centre, King's College London, London SE1 9NH, UK
| | - Sucharitha Balu
- King's Genomic Centre, King's College London, London SE1 9NH, UK
| | - Valeria Leon Kropf
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Rajesh K Mistry
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Ajay M Shah
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Giovanni E Mann
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
| | - Alison C Brewer
- British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK
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45
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Choudhry H, Harris AL. Advances in Hypoxia-Inducible Factor Biology. Cell Metab 2018; 27:281-298. [PMID: 29129785 DOI: 10.1016/j.cmet.2017.10.005] [Citation(s) in RCA: 588] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 08/03/2017] [Accepted: 10/12/2017] [Indexed: 12/14/2022]
Abstract
Hypoxia-inducible factor (HIF), a central regulator for detecting and adapting to cellular oxygen levels, transcriptionally activates genes modulating oxygen homeostasis and metabolic activation. Beyond this, HIF influences many other processes. Hypoxia, in part through HIF-dependent mechanisms, influences epigenetic factors, including DNA methylation and histone acetylation, which modulate hypoxia-responsive gene expression in cells. Hypoxia profoundly affects expression of many noncoding RNAs classes that have clinicopathological implications in cancer. HIF can regulate noncoding RNAs production, while, conversely, noncoding RNAs can modulate HIF expression. There is recent evidence for crosstalk between circadian rhythms and hypoxia-induced signaling, suggesting involvement of molecular clocks in adaptation to fluxes in nutrient and oxygen sensing. HIF induces increased production of cellular vesicles facilitating intercellular communication at a distance-for example, promoting angiogenesis in hypoxic tumors. Understanding the complex networks underlying cellular and genomic regulation in response to hypoxia via HIF may identify novel and specific therapeutic targets.
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Affiliation(s)
- Hani Choudhry
- Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Adrian L Harris
- Molecular Oncology Laboratories, Department of Oncology, University of Oxford, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, UK.
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46
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Assenov Y, Brocks D, Gerhäuser C. Intratumor heterogeneity in epigenetic patterns. Semin Cancer Biol 2018; 51:12-21. [PMID: 29366906 DOI: 10.1016/j.semcancer.2018.01.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/24/2017] [Accepted: 01/17/2018] [Indexed: 02/08/2023]
Abstract
Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. As a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. Profiling these variants contributes to understanding tumors' clonal origins and might help to better understand response to therapy. However, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity. Understanding epigenetic diversity across cancer cells provides important additional information about the functional state of subclones and therefore allows better understanding of tumor evolution and resistance to current therapies.
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Affiliation(s)
- Yassen Assenov
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - David Brocks
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Clarissa Gerhäuser
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
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47
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Epigenetics in teleost fish: From molecular mechanisms to physiological phenotypes. Comp Biochem Physiol B Biochem Mol Biol 2018; 224:210-244. [PMID: 29369794 DOI: 10.1016/j.cbpb.2018.01.006] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 01/08/2018] [Accepted: 01/16/2018] [Indexed: 02/07/2023]
Abstract
While the field of epigenetics is increasingly recognized to contribute to the emergence of phenotypes in mammalian research models across different developmental and generational timescales, the comparative biology of epigenetics in the large and physiologically diverse vertebrate infraclass of teleost fish remains comparatively understudied. The cypriniform zebrafish and the salmoniform rainbow trout and Atlantic salmon represent two especially important teleost orders, because they offer the unique possibility to comparatively investigate the role of epigenetic regulation in 3R and 4R duplicated genomes. In addition to their sequenced genomes, these teleost species are well-characterized model species for development and physiology, and therefore allow for an investigation of the role of epigenetic modifications in the emergence of physiological phenotypes during an organism's lifespan and in subsequent generations. This review aims firstly to describe the evolution of the repertoire of genes involved in key molecular epigenetic pathways including histone modifications, DNA methylation and microRNAs in zebrafish, rainbow trout, and Atlantic salmon, and secondly, to discuss recent advances in research highlighting a role for molecular epigenetics in shaping physiological phenotypes in these and other teleost models. Finally, by discussing themes and current limitations of the emerging field of teleost epigenetics from both theoretical and technical points of view, we will highlight future research needs and discuss how epigenetics will not only help address basic research questions in comparative teleost physiology, but also inform translational research including aquaculture, aquatic toxicology, and human disease.
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48
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Refined control of cell stemness allowed animal evolution in the oxic realm. Nat Ecol Evol 2018; 2:220-228. [DOI: 10.1038/s41559-017-0410-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/10/2017] [Indexed: 12/26/2022]
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49
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Chen R, Xu M, Nagati J, Garcia JA. Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells. PLoS One 2017; 12:e0190241. [PMID: 29281714 PMCID: PMC5744998 DOI: 10.1371/journal.pone.0190241] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 12/11/2017] [Indexed: 11/18/2022] Open
Abstract
Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2α (HIF-2α) subunit by the acetyltransferase/coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2α complex formation. In addition to promoting de novo transcription, Cbp and HIF-2α act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis.
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Affiliation(s)
- Rui Chen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Min Xu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Jason Nagati
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Joseph A. Garcia
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
- Department of Medicine, VA North Texas Health Care System, Dallas, Texas, United States of America
- * E-mail:
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Tyulkova EI, Vetrovoy OV, Sarieva KV, Vataeva LA, Glushchenko TS. The characteristics of acetylation of histone H3 at Lys24 in the hippocampus and neocortex of rats that were exposed to hypoxic stress at different stages of prenatal development. NEUROCHEM J+ 2017. [DOI: 10.1134/s1819712417040109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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