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1
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Yuan VG. Rhythms in Remodeling: Posttranslational Regulation of Bone by the Circadian Clock. Biomedicines 2025; 13:705. [PMID: 40149680 PMCID: PMC11940027 DOI: 10.3390/biomedicines13030705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
The circadian clock is a fundamental timekeeping system that regulates rhythmic biological processes in response to environmental light-dark cycles. In mammals, core clock genes (CLOCK, BMAL1, PER, and CRY) orchestrate these rhythms through transcriptional-translational feedback loops, influencing various physiological functions, including bone remodeling. Bone homeostasis relies on the coordinated activities of osteoblasts, osteoclasts, and osteocytes, with increasing evidence highlighting the role of circadian regulation in maintaining skeletal integrity. Disruptions in circadian rhythms are linked to bone disorders such as osteoporosis. Posttranslational modifications (PTMs), including phosphorylation, acetylation, and ubiquitination, serve as crucial regulators of both circadian mechanisms and bone metabolism. However, the specific role of PTMs in integrating circadian timing with bone remodeling remains underexplored. This review examines the intersection of circadian regulation and PTMs in bone biology, elucidating their impact on bone cell function and homeostasis. Understanding these interactions may uncover novel therapeutic targets for skeletal diseases associated with circadian disruptions.
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Affiliation(s)
- Vincent G Yuan
- Department of Otolaryngology-Head & Neck Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
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2
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Putthanbut N, Su PAB, Lee JY, Borlongan CV. Circadian rhythms in stem cells and their therapeutic potential. Stem Cell Res Ther 2025; 16:85. [PMID: 39988679 PMCID: PMC11849187 DOI: 10.1186/s13287-025-04178-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/23/2025] [Indexed: 02/25/2025] Open
Abstract
Circadian rhythms are present in almost all cells, but their existence in stem cells has remains not well established. Circadian clock appears to be closely associated with differentiated mature cells and rarely detected in immature embryonic stem cells. Recent evidence reveals the presence of circadian genes and rhythmic physiologic activities in stem cells as well as stem cell-derived extracellular vesicle (EV) characteristics. The circadian clock entails diverse physiologic and pathological mechanisms underlying cell fate. Integration of circadian rhythm to clinical applications, such as chronotherapy, chrono-biomarker, and environment modification, may facilitate therapeutic outcomes of stem cell-based regenerative medicine. Understanding circadian rhythms in stem cells can optimize stem cell-based therapies by determining the best times for harvesting and administering stem cells, thereby enhancing therapeutic efficacy. Further research into the circadian properties of stem cells will refine stem cell-based therapies, contributing to advancements in regenerative medicine.
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Affiliation(s)
- Napasiri Putthanbut
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Salaya, Thailand
| | - Paul Alexis Bourgade Su
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, USA
- Centro de Investigación en Ciencias de La Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Naucalpan, Mexico
| | - Jea-Young Lee
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, USA
| | - Cesario V Borlongan
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, USA.
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3
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Sharma SA, Oladejo SO, Kuang Z. Chemical interplay between gut microbiota and epigenetics: Implications in circadian biology. Cell Chem Biol 2025; 32:61-82. [PMID: 38776923 PMCID: PMC11569273 DOI: 10.1016/j.chembiol.2024.04.016] [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: 12/15/2023] [Revised: 03/22/2024] [Accepted: 04/26/2024] [Indexed: 05/25/2024]
Abstract
Circadian rhythms are intrinsic molecular mechanisms that synchronize biological functions with the day/night cycle. The mammalian gut is colonized by a myriad of microbes, collectively named the gut microbiota. The microbiota impacts host physiology via metabolites and structural components. A key mechanism is the modulation of host epigenetic pathways, especially histone modifications. An increasing number of studies indicate the role of the microbiota in regulating host circadian rhythms. However, the mechanisms remain largely unknown. Here, we summarize studies on microbial regulation of host circadian rhythms and epigenetic pathways, highlight recent findings on how the microbiota employs host epigenetic machinery to regulate circadian rhythms, and discuss its impacts on host physiology, particularly immune and metabolic functions. We further describe current challenges and resources that could facilitate research on microbiota-epigenetic-circadian rhythm interactions to advance our knowledge of circadian disorders and possible therapeutic avenues.
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Affiliation(s)
- Samskrathi Aravinda Sharma
- Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA
| | - Sarah Olanrewaju Oladejo
- Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA
| | - Zheng Kuang
- Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA.
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4
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Mao W, Ge X, Chen Q, Li JD. Epigenetic Mechanisms in the Transcriptional Regulation of Circadian Rhythm in Mammals. BIOLOGY 2025; 14:42. [PMID: 39857273 PMCID: PMC11762092 DOI: 10.3390/biology14010042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/27/2025]
Abstract
Almost all organisms, from the simplest bacteria to advanced mammals, havea near 24 h circadian rhythm. Circadian rhythms are highly conserved across different life forms and are regulated by circadian genes as well as by related transcription factors. Transcription factors are fundamental to circadian rhythms, influencing gene expression, behavior in plants and animals, and human diseases. This review examines the foundational research on transcriptional regulation of circadian rhythms, emphasizing histone modifications, chromatin remodeling, and Pol II pausing control. These studies have enhanced our understanding of transcriptional regulation within biological circadian rhythms and the importance of circadian biology in human health. Finally, we summarize the progress and challenges in these three areas of regulation to move the field forward.
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Affiliation(s)
- Wei Mao
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310000, China; (W.M.); (X.G.)
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310000, China
| | - Xingnan Ge
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310000, China; (W.M.); (X.G.)
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310000, China
| | - Qianping Chen
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310000, China; (W.M.); (X.G.)
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310000, China
| | - Jia-Da Li
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
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5
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Das S, Khan R, Banerjee S, Ray S, Ray S. Alterations in Circadian Rhythms, Sleep, and Physical Activity in COVID-19: Mechanisms, Interventions, and Lessons for the Future. Mol Neurobiol 2024; 61:10115-10137. [PMID: 38702566 DOI: 10.1007/s12035-024-04178-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 04/04/2024] [Indexed: 05/06/2024]
Abstract
Although the world is acquitting from the throes of COVID-19 and returning to the regularity of life, its effects on physical and mental health are prominently evident in the post-pandemic era. The pandemic subjected us to inadequate sleep and physical activities, stress, irregular eating patterns, and work hours beyond the regular rest-activity cycle. Thus, perturbing the synchrony of the regular circadian clock functions led to chronic psychiatric and neurological disorders and poor immunological response in several COVID-19 survivors. Understanding the links between the host immune system and viral replication machinery from a clock-infection biology perspective promises novel avenues of intervention. Behavioral improvements in our daily lifestyle can reduce the severity and expedite the convalescent stage of COVID-19 by maintaining consistent eating, sleep, and physical activity schedules. Including dietary supplements and nutraceuticals with prophylactic value aids in combating COVID-19, as their deficiency can lead to a higher risk of infection, vulnerability, and severity of COVID-19. Thus, besides developing therapeutic measures, perpetual healthy practices could also contribute to combating the upcoming pandemics. This review highlights the impact of the COVID-19 pandemic on biological rhythms, sleep-wake cycles, physical activities, and eating patterns and how those disruptions possibly contribute to the response, severity, and outcome of SARS-CoV-2 infection.
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Affiliation(s)
- Sandip Das
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, 502284, Telangana, India
| | - Rajni Khan
- National Institute of Pharmaceutical Education and Research (NIPER) - Hajipur, Vaishali, Hajipur, 844102, Bihar, India
| | - Srishti Banerjee
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, 502284, Telangana, India
| | - Shashikant Ray
- Department of Biotechnology, Mahatma Gandhi Central University, Motihari, 845401, India.
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Sandipan Ray
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, 502284, Telangana, India.
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6
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Torres M, Kirchner M, Marks CG, Mertins P, Kramer A. Proteomic insights into circadian transcription regulation: novel E-box interactors revealed by proximity labeling. Genes Dev 2024; 38:1020-1032. [PMID: 39562139 PMCID: PMC11610934 DOI: 10.1101/gad.351836.124] [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: 04/18/2024] [Accepted: 10/23/2024] [Indexed: 11/21/2024]
Abstract
Circadian clocks (∼24 h) are responsible for daily physiological, metabolic, and behavioral changes. Central to these oscillations is the regulation of gene transcription. Previous research has identified clock protein complexes that interact with the transcriptional machinery to orchestrate circadian transcription, but technological constraints have limited the identification of de novo proteins. Here we use a novel genomic locus-specific quantitative proteomics approach to provide a new perspective on time of day-dependent protein binding at a critical chromatin locus involved in circadian transcription: the E-box. Using proximity labeling proteomics at the E-box of the clock-controlled Dbp gene in mouse fibroblasts, we identified 69 proteins at this locus at the time of BMAL1 binding. This method successfully enriched BMAL1 as well as HDAC3 and HISTONE H2A.V/Z, known circadian regulators. New E-box proteins include the MINK1 kinase and the transporters XPO7 and APPL1, whose depletion in human U-2 OS cells results in disrupted circadian rhythms, suggesting a role in the circadian transcriptional machinery. Overall, our approach uncovers novel circadian modulators and provides a new strategy to obtain a complete temporal picture of circadian transcriptional regulation.
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Affiliation(s)
- Manon Torres
- Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Marieluise Kirchner
- Core Unit Proteomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Caroline G Marks
- Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Philipp Mertins
- Core Unit Proteomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Achim Kramer
- Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany;
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7
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Duan CY, Li Y, Zhi HY, Tian Y, Huang ZY, Chen SP, Zhang Y, Liu Q, Zhou L, Jiang XG, Ullah K, Guo Q, Liu ZH, Xu Y, Han JH, Hou J, O'Connor DP, Xu G. E3 ubiquitin ligase UBR5 modulates circadian rhythm by facilitating the ubiquitination and degradation of the key clock transcription factor BMAL1. Acta Pharmacol Sin 2024; 45:1793-1808. [PMID: 38740904 PMCID: PMC11336169 DOI: 10.1038/s41401-024-01290-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 04/10/2024] [Indexed: 05/16/2024]
Abstract
The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila, could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila. PER2-luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification level, offering potential insights into the modulation of the dysregulated circadian rhythm.
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Affiliation(s)
- Chun-Yan Duan
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St Stephen's Green, Dublin 2, D02 YN77, Dublin, Ireland
| | - Yue Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Hao-Yu Zhi
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Yao Tian
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, 2 Sipailou Road, Nanjing, 210096, China
| | - Zheng-Yun Huang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou, 215123, China
| | - Su-Ping Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Yang Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Qing Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Liang Zhou
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Xiao-Gang Jiang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Kifayat Ullah
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Qing Guo
- Department of Human Anatomy and Cytoneurobiology, Medical School of Soochow University, Suzhou, 215123, China
| | - Zhao-Hui Liu
- Department of Human Anatomy and Cytoneurobiology, Medical School of Soochow University, Suzhou, 215123, China
| | - Ying Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou, 215123, China
| | - Jun-Hai Han
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, 2 Sipailou Road, Nanjing, 210096, China
| | - Jiajie Hou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Darran P O'Connor
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St Stephen's Green, Dublin 2, D02 YN77, Dublin, Ireland
| | - Guoqiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China.
- Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
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8
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Xie X, Zhang M, Luo H. Regulation of metabolism by circadian rhythms: Support from time-restricted eating, intestinal microbiota & omics analysis. Life Sci 2024; 351:122814. [PMID: 38857654 DOI: 10.1016/j.lfs.2024.122814] [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: 02/18/2024] [Revised: 05/05/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Circadian oscillatory system plays a key role in coordinating the metabolism of most organisms. Perturbation of genetic effects and misalignment of circadian rhythms result in circadian dysfunction and signs of metabolic disorders. The eating-fasting cycle can act on the peripheral circadian clocks, bypassing the photoperiod. Therefore, time-restricted eating (TRE) can improve metabolic health by adjusting eating rhythms, a process achieved through reprogramming of circadian genomes and metabolic programs at different tissue levels or remodeling of the intestinal microbiota, with omics technology allowing visualization of the regulatory processes. Here, we review recent advances in circadian regulation of metabolism, focus on the potential application of TRE for rescuing circadian dysfunction and metabolic disorders with the contribution of intestinal microbiota in between, and summarize the significance of omics technology.
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Affiliation(s)
- Ximei Xie
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, PR China
| | - Mengjie Zhang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, PR China
| | - Hailing Luo
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, PR China.
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9
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Wang B, Adamo ME, Zhou X, Wang Z, Gerber SA, Kettenbach AN, Dunlap JC. Acetylation of WCC is dispensable for the core circadian clock but differentially regulates acute light responses in Neurospora. J Biol Chem 2024; 300:107508. [PMID: 38944116 PMCID: PMC11325773 DOI: 10.1016/j.jbc.2024.107508] [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: 12/08/2023] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/01/2024] Open
Abstract
In the Neurospora circadian system, the White Collar Complex (WCC) formed by WC-1 and WC-2 drives expression of the frequency (frq) gene whose product FRQ feedbacks to inhibit transcriptional activity of WCC. Phosphorylation of WCC has been extensively studied, but the extent and significance of other post-translational modifications (PTM) have been poorly studied. To this end, we used mass-spectrometry to study alkylation sites on WCC, resulting in discovery of nine acetylation sites. Mutagenesis analysis showed most of the acetylation events individually do not play important roles in period determination. Moreover, mutating all the lysines falling in either half of WC-1 or all the lysine residues in WC-2 to arginines did not abolish circadian rhythms. In addition, we also found nine mono-methylation sites on WC-1, but like acetylation, individual ablation of most of the mono-methylation events did not result in a significant period change. Taken together, the data here suggest that acetylation or mono-methylation on WCC is not a determinant of the pace of the circadian feedback loop. The finding is consistent with a model in which repression of WCC's circadian activity is mainly controlled by phosphorylation. Interestingly, light-induced expression of some light-responsive genes has been modulated in certain wc-1 acetylation mutants, suggesting that WC-1 acetylation events differentially regulate light responses.
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Affiliation(s)
- Bin Wang
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
| | - Mark E Adamo
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA
| | - Xiaoying Zhou
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Ziyan Wang
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Scott A Gerber
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA; Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Arminja N Kettenbach
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Jay C Dunlap
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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10
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Murgo E, Falco G, Serviddio G, Mazzoccoli G, Colangelo T. Circadian patterns of growth factor receptor-dependent signaling and implications for carcinogenesis. Cell Commun Signal 2024; 22:319. [PMID: 38858728 PMCID: PMC11163765 DOI: 10.1186/s12964-024-01676-w] [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: 03/07/2024] [Accepted: 05/21/2024] [Indexed: 06/12/2024] Open
Abstract
Several different signaling pathways that regulate cell proliferation and differentiation are initiated by binding of ligands to cell-surface and membrane-bound enzyme-linked receptors, such as receptor tyrosine kinases and serine-threonine kinases. They prompt phosphorylation of tyrosine and serine-threonine residues and initiate downstream signaling pathways and priming of intracellular molecules that convey the signal in the cytoplasm and nucleus, with transcriptional activation of specific genes enriching cell growth and survival-related cascades. These cell processes are rhythmically driven by molecular clockworks endowed in every cell type and when deregulated play a crucial role in cancer onset and progression. Growth factors and their matching receptor-dependent signaling are frequently overexpressed and/or dysregulated in many cancer types. In this review we focus on the interplay between biological clocks and Growth Factor Receptor-dependent signaling in the context of carcinogenesis.
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Affiliation(s)
- Emanuele Murgo
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza",, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, 71013, Italy
| | - Giorgia Falco
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza",, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, 71013, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza",, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, 71013, Italy.
| | - Tommaso Colangelo
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
- Cancer Cell Signaling Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), San Giovanni Rotondo, Italy.
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11
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Luo B, Song J, Zhang J, Han J, Zhou X, Chen L. The contribution of circadian clock to the biological processes. Front Mol Biosci 2024; 11:1387576. [PMID: 38903177 PMCID: PMC11187296 DOI: 10.3389/fmolb.2024.1387576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 05/20/2024] [Indexed: 06/22/2024] Open
Abstract
All organisms have various circadian, behavioral, and physiological 24-h periodic rhythms, which are controlled by the circadian clock. The circadian clock controls various behavioral and physiological rhythms. In mammals, the primary circadian clock is present in the suprachiasmatic nucleus of the hypothalamus. The rhythm of the circadian clock is controlled by the interaction between negative and positive feedback loops, consisting of crucial clock regulators (including Bmal1 and Clock), three cycles (mPer1, mPer2, and mPer3), and two cryptochromes (Cry1 and Cry2). The development of early mammalian embryos is an ordered and complex biological process that includes stages from fertilized eggs to blastocysts and undergoes important morphological changes, such as blastocyst formation, cell multiplication, and compaction. The circadian clock affects the onset and timing of embryonic development. The circadian clock affects many biological processes, including eating time, immune function, sleep, energy metabolism, and endocrinology, therefore, it is also crucial for overall health, growth and development after birth. This review summarized the effects of the circadian clock in the body's physiological activities. A new strategy is proposed for the prevention of malformations or diseases by regulating the circadian clock or changing circadian rhythms.
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Affiliation(s)
- Beibei Luo
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Jiangyuan Song
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Jiaqi Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Jun Han
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Xin Zhou
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
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12
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Munteanu C, Turti S, Achim L, Muresan R, Souca M, Prifti E, Mârza SM, Papuc I. The Relationship between Circadian Rhythm and Cancer Disease. Int J Mol Sci 2024; 25:5846. [PMID: 38892035 PMCID: PMC11172077 DOI: 10.3390/ijms25115846] [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: 04/06/2024] [Revised: 05/25/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
The circadian clock regulates biological cycles across species and is crucial for physiological activities and biochemical reactions, including cancer onset and development. The interplay between the circadian rhythm and cancer involves regulating cell division, DNA repair, immune function, hormonal balance, and the potential for chronotherapy. This highlights the importance of maintaining a healthy circadian rhythm for cancer prevention and treatment. This article investigates the complex relationship between the circadian rhythm and cancer, exploring how disruptions to the internal clock may contribute to tumorigenesis and influence cancer progression. Numerous databases are utilized to conduct searches for articles, such as NCBI, MEDLINE, and Scopus. The keywords used throughout the academic archives are "circadian rhythm", "cancer", and "circadian clock". Maintaining a healthy circadian cycle involves prioritizing healthy sleep habits and minimizing disruptions, such as consistent sleep schedules, reduced artificial light exposure, and meal timing adjustments. Dysregulation of the circadian clock gene and cell cycle can cause tumor growth, leading to the need to regulate the circadian cycle for better treatment outcomes. The circadian clock components significantly impact cellular responses to DNA damage, influencing cancer development. Understanding the circadian rhythm's role in tumor diseases and their therapeutic targets is essential for treating and preventing cancer. Disruptions to the circadian rhythm can promote abnormal cell development and tumor metastasis, potentially due to immune system imbalances and hormonal fluctuations.
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Affiliation(s)
- Camelia Munteanu
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Sabina Turti
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Larisa Achim
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Raluca Muresan
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Marius Souca
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Eftimia Prifti
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Sorin Marian Mârza
- Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania;
| | - Ionel Papuc
- Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania;
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13
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Sharma D, Partch CL. PAS Dimerization at the Nexus of the Mammalian Circadian Clock. J Mol Biol 2024; 436:168341. [PMID: 37924861 PMCID: PMC11729053 DOI: 10.1016/j.jmb.2023.168341] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/23/2023] [Accepted: 10/29/2023] [Indexed: 11/06/2023]
Abstract
Circadian rhythms are genetically encoded molecular clocks for internal biological timekeeping. Organisms from single-cell bacteria to humans use these clocks to adapt to the external environment and synchronize their physiology and behavior to solar light/dark cycles. Although the proteins that constitute the molecular 'cogs' and give rise to circadian rhythms are now known, we still lack a detailed understanding of how these proteins interact to generate and sustain the ∼24-hour circadian clock. Structural studies have helped to expand the architecture of clock proteins and have revealed the abundance of the only well-defined structured regions in the mammalian clock called Per-ARNT-Sim (PAS) domains. PAS domains are modular, evolutionarily conserved sensory and signaling domains that typically mediate protein-protein interactions. In the mammalian circadian clock, PAS domains modulate homo and heterodimerization of several core clock proteins that assemble into transcription factors or repressors. This review will focus on the functional importance of the PAS domains in the circadian clock from a biophysical and biochemical standpoint and describe their roles in clock protein interactions and circadian timekeeping.
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Affiliation(s)
- Diksha Sharma
- Department of Chemistry and Biochemistry, University of California Santa Cruz, CA, United States
| | - Carrie L Partch
- Department of Chemistry and Biochemistry, University of California Santa Cruz, CA, United States; Center for Circadian Biology, University of California San Diego, CA, United States.
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14
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Hu Y, Li X, Zhang J, Liu D, Lu R, Li JD. A genome-wide CRISPR screen identifies USP1 as a novel regulator of the mammalian circadian clock. FEBS J 2024; 291:445-457. [PMID: 37909373 DOI: 10.1111/febs.16990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 09/07/2023] [Accepted: 10/27/2023] [Indexed: 11/03/2023]
Abstract
The circadian clock is generated by a molecular timekeeping mechanism coordinating daily oscillations of physiology and behaviors in mammals. In the mammalian circadian clockwork, basic helix-loop-helix ARNT-like protein 1 (BMAL1) is a core circadian component whose defects lead to circadian disruption and elicit behavioral arrhythmicity. To identify previously unknown regulators for circadian clocks, we searched for genes influencing BMAL1 protein level by using a CRISPR/Cas9-based genome-wide knockout library. As a result, we found that the deubiquitinase ubiquitin carboxyl-terminal hydrolase 1 (USP1) positively affects BMAL1 protein abundance. Overexpression of wild-type USP1, but not a deubiquitinase-inactive mutant USP1, upregulated BMAL1 protein level, whereas genetic ablation of USP1 downregulated BMAL1 protein level in U2OS cells. Furthermore, treatment with USP1 inhibitors led to significant downregulation of BMAL1 protein in U2OS cells as well as mouse tissues. Subsequently, genetic ablation or pharmacological inhibition of USP1 resulted in reduced mRNA levels of a panel of clock genes and disrupted circadian rhythms in U2OS cells. Mechanistically, USP1 was able to de-ubiquitinate BMAL1 and inhibit the proteasomal degradation of BMAL1. Interestingly, the expression of Usp1 was much higher than the other two deubiquitinases of BMAL1 (Usp2 and Usp9X) in the mouse heart, implying a tissue-specific function of USP1 in the regulation of BMAL1 stability. Our work thus identifies deubiquitinase USP1 as a previously unknown regulator of the mammalian circadian clock and highlights the potential of genome-wide CRISPR screens in the identification of regulators for the circadian clock.
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Affiliation(s)
- Ying Hu
- Furong Laboratory, Department of Anaesthesiology, Xiangya Hospital, Central South University, Changsha, China
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- MOE Key Laboratory of Rare Pediatric Diseases, Changsha, China
| | - Xin Li
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- MOE Key Laboratory of Rare Pediatric Diseases, Changsha, China
| | - Jing Zhang
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Dengfeng Liu
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Renbin Lu
- Furong Laboratory, Department of Anaesthesiology, Xiangya Hospital, Central South University, Changsha, China
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- Department of Basic Medical Sciences, Changsha Medical University, Changsha, China
- National Clinical Research Center for Geratric Disorder, Xiangya Hospital, Central South University, Changsha, China
| | - Jia-Da Li
- Furong Laboratory, Department of Anaesthesiology, Xiangya Hospital, Central South University, Changsha, China
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- MOE Key Laboratory of Rare Pediatric Diseases, Changsha, China
- Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, China
- National Clinical Research Center for Geratric Disorder, Xiangya Hospital, Central South University, Changsha, China
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15
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Surme S, Ergun C, Gul S, Akyel YK, Gul ZM, Ozcan O, Ipek OS, Akarlar BA, Ozlu N, Taskin AC, Turkay M, Gören AC, Baris I, Ozturk N, Guzel M, Aydin C, Okyar A, Kavakli IH. TW68, cryptochromes stabilizer, regulates fasting blood glucose levels in diabetic ob/ob and high fat-diet-induced obese mice. Biochem Pharmacol 2023; 218:115896. [PMID: 37898388 DOI: 10.1016/j.bcp.2023.115896] [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: 07/10/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 10/30/2023]
Abstract
Cryptochromes (CRYs), transcriptional repressors of the circadian clock in mammals, inhibit cAMP production when glucagon activates G-protein coupled receptors. Therefore, molecules that modulate CRYs have the potential to regulate gluconeogenesis. In this study, we discovered a new molecule called TW68 that interacts with the primary pockets of mammalian CRY1/2, leading to reduced ubiquitination levels and increased stability. In cell-based circadian rhythm assays using U2OS Bmal1-dLuc cells, TW68 extended the period length of the circadian rhythm. Additionally, TW68 decreased the transcriptional levels of two genes, Phosphoenolpyruvate carboxykinase 1 (PCK1) and Glucose-6-phosphatase (G6PC), which play crucial roles in glucose biosynthesis during glucagon-induced gluconeogenesis in HepG2 cells. Oral administration of TW68 in mice showed good tolerance, a good pharmacokinetic profile, and remarkable bioavailability. Finally, when administered to fasting diabetic animals from ob/ob and HFD-fed obese mice, TW68 reduced blood glucose levels by enhancing CRY stabilization and subsequently decreasing the transcriptional levels of Pck1 and G6pc. These findings collectively demonstrate the antidiabetic efficacy of TW68 in vivo, suggesting its therapeutic potential for controlling fasting glucose levels in the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Saliha Surme
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Cagla Ergun
- Department of Chemical and Biological Engineering, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Seref Gul
- Istanbul University, Department of Biology, Biotechnology Division, TR-34116 Beyazit-İstanbul, Türkiye; Current address: Bezmialem Vakif University, Institute of Life Sciences and Biotechnology, Beykoz, Istanbul, Türkiye
| | - Yasemin Kubra Akyel
- Istanbul Medipol University, School of Medicine, Department of Medical Pharmacology, İstanbul, Türkiye; Istanbul University, Faculty of Pharmacy Department of Pharmacology, TR-34116 Beyazit-İstanbul, Türkiye
| | - Zeynep Melis Gul
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Onur Ozcan
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Ozgecan Savlug Ipek
- Istanbul Medipol University, Regenerative and Restorative Medicine Research Center (REMER), Kavacik Campus, Kavacik-Beykoz/İstanbul 34810, Türkiye
| | - Busra Aytul Akarlar
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Nurhan Ozlu
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Ali Cihan Taskin
- Department of Laboratory Animal Science, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye
| | - Metin Turkay
- Department of Industrial Engineering, Koc University, Rumelifeneri Yolu, İstanbul, Türkiye
| | - Ahmet Ceyhan Gören
- Gebze Technical University, Department of Chemistry, Gebze, Kocaeli, Türkiye
| | - Ibrahim Baris
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye
| | - Nuri Ozturk
- Gebze Technical University, Department of Molecular Biology and Genetics, Gebze, Kocaeli, Türkiye
| | - Mustafa Guzel
- Istanbul Medipol University, Regenerative and Restorative Medicine Research Center (REMER), Kavacik Campus, Kavacik-Beykoz/İstanbul 34810, Türkiye
| | - Cihan Aydin
- Department of Molecular Biology and Genetics, Istanbul Medeniyet University, Istanbul, Türkiye
| | - Alper Okyar
- Istanbul University, Faculty of Pharmacy Department of Pharmacology, TR-34116 Beyazit-İstanbul, Türkiye
| | - Ibrahim Halil Kavakli
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye; Department of Chemical and Biological Engineering, Koc University, Rumelifeneri Yolu, Istanbul, Türkiye.
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16
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Wang B, Edamo ME, Zhou X, Wang Z, Gerber SA, Kettenbach AN, Dunlap JC. Acetylation of WCC is dispensable for the core circadian clock but differentially regulates acute light responses in Neurospora. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.29.569266. [PMID: 38076981 PMCID: PMC10705461 DOI: 10.1101/2023.11.29.569266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/09/2024]
Abstract
In the Neurospora circadian system, the White Collar Complex (WCC) formed by WC-1 and WC-2 drives expression of the frequency ( frq ) gene whose product FRQ feedbacks to inhibit transcriptional activity of WCC. Phosphorylation of WCC has been extensively studied, but the extent and significance of other post-translational modifications (PTM) has been poorly studied. To this end, we used mass-spectrometry to study alkylation sites on WCC, resulting in discovery of nine acetylation sites. Mutagenesis analysis showed most of the acetylation events individually do not play important roles in period determination. Moreover, mutating all the lysines falling in either half of WC-1 or all the lysine residues in WC-2 to arginines did not abolish circadian rhythms. In addition, we also found nine mono-methylation sites on WC-1, but like acetylation, individual ablation of most of the mono-methylation events did not result in a significant period change. Taken together, the data here suggest that acetylation or mono-methylation on WCC is not a determinant of the pace of the circadian feedback loop. The finding is consistent with a model in which repression of WCC's circadian activity is controlled mainly by phosphorylation. Interestingly, light-induced expression of some light-responsive genes has been modulated in certain wc-1 acetylation mutants, suggesting that WC-1 acetylation events differentially regulate light responses.
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17
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Abstract
Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 14.2% of all diagnosed tumors and 50.1% of all malignant tumors, and the median survival time is approximately 8 months irrespective of whether a patient receives treatment without significant improvement despite expansive research (Ostrom QT, Price M, Neff C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neurooncology. 2022; 24(suppl 5):v1-v95.). Recently, important roles for the circadian clock in GBM tumorigenesis have been reported. Positive regulators of circadian-controlled transcription, brain and muscle ARNT-like 1 (BMAL1), and circadian locomotor output cycles kaput (CLOCK), are highly expressed also in GBM and correlated with poor patient prognosis. BMAL1 and CLOCK promote the maintenance of GBM stem cells (GSCs) and the establishment of a pro-tumorigenic tumor microenvironment (TME), suggesting that targeting the core clock proteins may augment GBM treatment. Here, we review findings that highlight the critical role the circadian clock plays in GBM biology and the strategies by which the circadian clock can be leveraged for GBM treatment in the clinic moving forward.
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Affiliation(s)
- Priscilla Chan
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Jeremy N Rich
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Steve A Kay
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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18
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Murgo E, Colangelo T, Bellet MM, Malatesta F, Mazzoccoli G. Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology. BIOLOGY 2023; 12:1354. [PMID: 37887064 PMCID: PMC10603908 DOI: 10.3390/biology12101354] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/14/2023] [Accepted: 10/20/2023] [Indexed: 10/28/2023]
Abstract
Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix-loop-helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 is a core cog of the molecular clockwork and plays a regulatory role on metabolic pathways, is important for the function of the central nervous system in mammals, and is involved in carcinogenesis as well as in normal biological functions and processes, such as cardiovascular function and wound healing. We reviewed the scientific literature addressing the various facets of NPAS2 and framing this gene/protein in several and very different research and clinical fields.
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Affiliation(s)
- Emanuele Murgo
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy;
| | - Tommaso Colangelo
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71100 Foggia, Italy;
- Cancer Cell Signaling Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy
| | - Maria Marina Bellet
- Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy;
| | - Francesco Malatesta
- Department of Biochemical Sciences “Alessandro Rossi Fanelli”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy;
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19
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Jiang H, Wang X, Ma J, Xu G. The fine-tuned crosstalk between lysine acetylation and the circadian rhythm. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194958. [PMID: 37453648 DOI: 10.1016/j.bbagrm.2023.194958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Circadian rhythm is a roughly 24-h wake and sleep cycle that almost all of the organisms on the earth follow when they execute their biological functions and physiological activities. The circadian clock is mainly regulated by the transcription-translation feedback loop (TTFL), consisting of the core clock proteins, including BMAL1, CLOCK, PERs, CRYs, and a series of accessory factors. The circadian clock and the downstream gene expression are not only controlled at the transcriptional and translational levels but also precisely regulated at the post-translational modification level. Recently, it has been discovered that CLOCK exhibits lysine acetyltransferase activities and could acetylate protein substrates. Core clock proteins are also acetylated, thereby altering their biological functions in the regulation of the expression of downstream genes. Studies have revealed that many protein acetylation events exhibit oscillation behavior. However, the biological function of acetylation on circadian rhythm has only begun to explore. This review will briefly introduce the acetylation and deacetylation of the core clock proteins and summarize the proteins whose acetylation is regulated by CLOCK and circadian rhythm. Then, we will also discuss the crosstalk between lysine acetylation and the circadian clock or other post-translational modifications. Finally, we will briefly describe the possible future perspectives in the field.
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Affiliation(s)
- Honglv Jiang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xiaohui Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Jingjing Ma
- Department of Pharmacy, Medical Center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215123, China.
| | - Guoqiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China.
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20
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Sato S, Hishida T, Kinouchi K, Hatanaka F, Li Y, Nguyen Q, Chen Y, Wang PH, Kessenbrock K, Li W, Izpisua Belmonte JC, Sassone-Corsi P. The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming. Cell Rep 2023; 42:112590. [PMID: 37261952 DOI: 10.1016/j.celrep.2023.112590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/28/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023] Open
Abstract
Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.
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Affiliation(s)
- Shogo Sato
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA; Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, TX, USA.
| | - Tomoaki Hishida
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan
| | - Kenichiro Kinouchi
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Fumiaki Hatanaka
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA
| | - Yumei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Quy Nguyen
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Yumay Chen
- UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Ping H Wang
- UC Irvine Diabetes Center, Sue and Bill Gross Stem Cell Research Center, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Kai Kessenbrock
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Juan Carlos Izpisua Belmonte
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Altos Labs, San Diego, CA, USA.
| | - Paolo Sassone-Corsi
- Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
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21
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Abstract
Shift work can cause circadian cycles disturbances and misaligns the endogenous rhythms. The physiological variables are driven by the circadian system and, its misalignment, can impair the metabolic functions. Thus, the main objective of this study was to evaluate the metabolic alterations as a result of shift work and night work reported in articles published in the last 5 years, using the eligibility criteria both gender and indexed articles in English language. In order to execute this work, we perform a systematic review according to PRISMA guidelines and searched about Chronobiology Disorders and Night Work, both related to metabolism, in Medline, Lilacs, ScienceDirect and Cochrane. Cross-sectional, cohort and experimental studies with low risk of bias were included. We found a total of 132 articles, and, after the selection process, 16 articles remained to be analyzed. It was observed that shift work can cause circadian misalignment and, consequently, some metabolic parameters alterations such as an impaired glycemic control and insulin functioning, cortisol phase release, cholesterol fractions imbalance, changes in morphological indexes and melatonin secretion. There are some limitations, such as heterogenicity in used databases and the 5 years restriction period, because the effects of sleep disturbance may have been reported earlier. In conclusion, we suggest that shift work interferes with the sleep-wake cycle and eating patterns, which cause crucial physiological alterations that, together, can lead to metabolic syndrome.
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Affiliation(s)
| | | | - Bruna Del Vechio Koike
- Department of Medicine, Medical School, Federal University of São Francisco Valley, Petrolina, PE, Brazil
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Ortega-Campos SM, Verdugo-Sivianes EM, Amiama-Roig A, Blanco JR, Carnero A. Interactions of circadian clock genes with the hallmarks of cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188900. [PMID: 37105413 DOI: 10.1016/j.bbcan.2023.188900] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/12/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023]
Abstract
The molecular machinery of the circadian clock regulates the expression of many genes and processes in the organism, allowing the adaptation of cellular activities to the daily light-dark cycles. Disruption of the circadian rhythm can lead to various pathologies, including cancer. Thus, disturbance of the normal circadian clock at both genetic and environmental levels has been described as an independent risk factor for cancer. In addition, researchers have proposed that circadian genes may have a tissue-dependent and/or context-dependent role in tumorigenesis and may function both as tumor suppressors and oncogenes. Finally, circadian clock core genes may trigger or at least be involved in different hallmarks of cancer. Hence, expanding the knowledge of the molecular basis of the circadian clock would be helpful to identify new prognostic markers of tumorigenesis and potential therapeutic targets.
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Affiliation(s)
- Sara M Ortega-Campos
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville 41013, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Eva M Verdugo-Sivianes
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville 41013, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Ana Amiama-Roig
- Hospital Universitario San Pedro, Logroño 26006, Spain; Centro de Investigación Biomédica de La Rioja (CIBIR), Logroño 26006, Spain
| | - José R Blanco
- Hospital Universitario San Pedro, Logroño 26006, Spain; Centro de Investigación Biomédica de La Rioja (CIBIR), Logroño 26006, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville 41013, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid 28029, Spain.
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23
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Zhu Y, Liu Y, Escames G, Yang Z, Zhao H, Qian L, Xue C, Xu D, Acuña-Castroviejo D, Yang Y. Deciphering clock genes as emerging targets against aging. Ageing Res Rev 2022; 81:101725. [PMID: 36029999 DOI: 10.1016/j.arr.2022.101725] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/21/2022] [Accepted: 08/22/2022] [Indexed: 01/31/2023]
Abstract
The old people often suffer from circadian rhythm disturbances, which in turn accelerate aging. Many aging-related degenerative diseases such as Alzheimer's disease, Parkinson's disease, and osteoarthritis have an inextricable connection with circadian rhythm. In light of the predominant effects of clock genes on regulating circadian rhythm, we systematically present the elaborate network of roles that clock genes play in aging in this review. First, we briefly introduce the basic background regarding clock genes. Second, we systemically summarize the roles of clock genes in aging and aging-related degenerative diseases. Third, we discuss the relationship between clock genes polymorphisms and aging. In summary, this review is intended to clarify the indispensable roles of clock genes in aging and sheds light on developing clock genes as anti-aging targets.
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Affiliation(s)
- Yanli Zhu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yanqing Liu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Germaine Escames
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, Avda. del Conocimiento s/n, Granada, Spain; Ibs. Granada and CIBERfes, Granada, Spain; UGC of Clinical Laboratories, Universitu San Cecilio's Hospital, Granada, Spain
| | - Zhi Yang
- Department of General Surgery, Tangdu Hospital, The Airforce Medical University, 1 Xinsi Road, Xi'an, China
| | - Huadong Zhao
- Department of General Surgery, Tangdu Hospital, The Airforce Medical University, 1 Xinsi Road, Xi'an, China
| | - Lu Qian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Chengxu Xue
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Danni Xu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Darío Acuña-Castroviejo
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, Avda. del Conocimiento s/n, Granada, Spain; Ibs. Granada and CIBERfes, Granada, Spain; UGC of Clinical Laboratories, Universitu San Cecilio's Hospital, Granada, Spain.
| | - Yang Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China.
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24
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Nakahata Y, Fukada Y. Molecular connections between circadian clock and health/aging. J Biochem 2022; 171:473-476. [PMID: 35383844 DOI: 10.1093/jb/mvac028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/11/2022] [Indexed: 11/14/2022] Open
Abstract
For decades, considerable efforts have been expended for solving the molecular mechanisms of disease progression. An important clue to tackle this question is the circadian clock. Recent findings have uncovered previously unknown molecular connections between circadian clock and disease incidence, consequently causing the aging process. Furthermore, "chronotherapy" is emerging as a new concept of optimizing the time of the day for drug administration according to target gene expressions in order to maximize therapeutic efficacy and minimize the side effects. This concept will help cure patients and prevent them from suffering evitable pain and side effects. This JB special issue "Molecular connections between circadian clock and health/aging" discusses how the circadian clocks link to health and aging from molecular to organismal levels.
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Affiliation(s)
- Yasukazu Nakahata
- Department of Neurobiology & Behavior, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Yoshitaka Fukada
- Department of Biological Sciences, School of Science
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
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25
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Malik S, Stokes Iii J, Manne U, Singh R, Mishra MK. Understanding the significance of biological clock and its impact on cancer incidence. Cancer Lett 2022; 527:80-94. [PMID: 34906624 PMCID: PMC8816870 DOI: 10.1016/j.canlet.2021.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022]
Abstract
The circadian clock is an essential timekeeper that controls, for humans, the daily rhythm of biochemical, physiological, and behavioral functions. Irregular performance or disruption in circadian rhythms results in various diseases, including cancer. As a factor in cancer development, perturbations in circadian rhythms can affect circadian homeostasis in energy balance, lead to alterations in the cell cycle, and cause dysregulation of chromatin remodeling. However, knowledge gaps remain in our understanding of the relationship between the circadian clock and cancer. Therefore, a mechanistic understanding by which circadian disruption enhances cancer risk is needed. This review article outlines the importance of the circadian clock in tumorigenesis and summarizes underlying mechanisms in the clock and its carcinogenic mechanisms, highlighting advances in chronotherapy for cancer treatment.
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Affiliation(s)
- Shalie Malik
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA; Department of Zoology and Dr. Giri Lal Gupta Institute of Public Health and Public Affairs, University of Lucknow, Lucknow, UP, India
| | - James Stokes Iii
- Department of Biological and Environmental Sciences, Auburn University, Montgomery, AL, USA
| | - Upender Manne
- Departments of Pathology, Surgery and Epidemiology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | - Manoj K Mishra
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA.
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26
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Tuning up an aged clock: Circadian clock regulation in metabolism and aging. TRANSLATIONAL MEDICINE OF AGING 2022. [DOI: 10.1016/j.tma.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Abstract
The modern way of life has dramatically affected our biological rhythms. Circadian rhythms, which are generated by an endogenous circadian clock, are observed in a large number of physiological functions including metabolism. Proper peripheral clock synchronization by different signals including appropriate feeding/fasting cycles is essential to coordinate and temporally gate metabolic processes. In this chapter, we emphasize the importance of nutrient sensing by peripheral clocks and highlight the major role of peripheral and central clock communication to locally regulate metabolic processes and ensure optimal energy storage and expenditure. As a consequence, changes in eating behavior and/or bedtime, as occurs upon shift work and jet lag, have direct consequences on metabolism and participate in the increasing prevalence of obesity and associated metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. In this setting, time-restricted feeding has been suggested as an efficient approach to ameliorate metabolic parameters and control body weight.
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Affiliation(s)
- Yasmine Sebti
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Aurore Hebras
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Benoit Pourcet
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - Hélène Duez
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
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28
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Tabibzadeh S. CircadiOmic medicine and aging. Ageing Res Rev 2021; 71:101424. [PMID: 34389481 DOI: 10.1016/j.arr.2021.101424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/22/2021] [Accepted: 08/05/2021] [Indexed: 01/15/2023]
Abstract
The earth displays daily, seasonal and annual environmental cycles that have led to evolutionarily adapted ultradian, circadian and infradian rhythmicities in the entire biosphere. All biological organisms must adapt to these cycles that synchronize the function of their circadiome. The objective of this review is to discuss the latest knowledge regarding the role of circadiomics in health and aging. The biological timekeepers are responsive to the environmental cues at microsecond to seasonal time-scales and act with precision of a clock machinery. The robustness of these rhythms is essential to normal daily function of cells, tissues and organs. Mis-alignment of circadian rhythms makes the individual prone to aging, sleep disorders, cancer, diabetes, and neuro-degenerative diseases. Circadian and CircadiOmic medicine are emerging fields that leverage our in-depth understanding of health issues, that arise as a result of disturbances in circadian rhythms, towards establishing better therapeutic approaches in personalized medicine and for geroprotection.
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Affiliation(s)
- Siamak Tabibzadeh
- Frontiers in Bioscience Research Institute in Aging and Cancer, 16471 Scientific Way, Irvine, CA 92618, United States.
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29
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Loh D, Reiter RJ. Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders. Antioxidants (Basel) 2021; 10:1483. [PMID: 34573116 PMCID: PMC8465482 DOI: 10.3390/antiox10091483] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid-liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.
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Affiliation(s)
- Doris Loh
- Independent Researcher, Marble Falls, TX 78654, USA
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229, USA
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30
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Nuclear Receptors and Clock Components in Cardiovascular Diseases. Int J Mol Sci 2021; 22:ijms22189721. [PMID: 34575881 PMCID: PMC8468608 DOI: 10.3390/ijms22189721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/04/2021] [Accepted: 09/06/2021] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular diseases (CVD) are still the first cause of death worldwide. Their main origin is the development of atherosclerotic plaque, which consists in the accumulation of lipids and inflammatory leucocytes within the vascular wall of large vessels. Beyond dyslipidemia, diabetes, obesity, hypertension and smoking, the alteration of circadian rhythms, in shift workers for instance, has recently been recognized as an additional risk factor. Accordingly, targeting a pro-atherogenic pathway at the right time window, namely chronotherapy, has proven its efficiency in reducing plaque progression without affecting healthy tissues in mice, thus providing the rationale of such an approach to treat CVD and to reduce drug side effects. Nuclear receptors are transcriptional factors involved in the control of many physiological processes. Among them, Rev-erbs and RORs control metabolic homeostasis, inflammatory processes and the biological clock. In this review, we discuss the opportunity to dampen atherosclerosis progression by targeting such ligand-activated core clock components in a (chrono-)therapeutic approach in order to treat CVD.
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31
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Parnell AA, De Nobrega AK, Lyons LC. Translating around the clock: Multi-level regulation of post-transcriptional processes by the circadian clock. Cell Signal 2021; 80:109904. [PMID: 33370580 PMCID: PMC8054296 DOI: 10.1016/j.cellsig.2020.109904] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/20/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022]
Abstract
The endogenous circadian clock functions to maintain optimal physiological health through the tissue specific coordination of gene expression and synchronization between tissues of metabolic processes throughout the 24 hour day. Individuals face numerous challenges to circadian function on a daily basis resulting in significant incidences of circadian disorders in the United States and worldwide. Dysfunction of the circadian clock has been implicated in numerous diseases including cancer, diabetes, obesity, cardiovascular and hepatic abnormalities, mood disorders and neurodegenerative diseases. The circadian clock regulates molecular, metabolic and physiological processes through rhythmic gene expression via transcriptional and post-transcriptional processes. Mounting evidence indicates that post-transcriptional regulation by the circadian clock plays a crucial role in maintaining tissue specific biological rhythms. Circadian regulation affecting RNA stability and localization through RNA processing, mRNA degradation, and RNA availability for translation can result in rhythmic protein synthesis, even when the mRNA transcripts themselves do not exhibit rhythms in abundance. The circadian clock also targets the initiation and elongation steps of translation through multiple pathways. In this review, the influence of the circadian clock across the levels of post-transcriptional, translation, and post-translational modifications are examined using examples from humans to cyanobacteria demonstrating the phylogenetic conservation of circadian regulation. Lastly, we briefly discuss chronotherapies and pharmacological treatments that target circadian function. Understanding the complexity and levels through which the circadian clock regulates molecular and physiological processes is important for future advancement of therapeutic outcomes.
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Affiliation(s)
- Amber A Parnell
- Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA
| | - Aliza K De Nobrega
- Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA
| | - Lisa C Lyons
- Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA.
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32
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Abstract
Circadian rhythms describe physiological systems that repeat themselves with a cycle of approximately 24 h. Our understanding of the cellular and molecular origins of these oscillations has improved dramatically, allowing us to appreciate the significant role these oscillations play in maintaining physiological homeostasis. Circadian rhythms allow living organisms to predict and efficiently respond to a dynamically changing environment, set by repetitive day/night cycles. Since circadian rhythms underlie almost every aspect of human physiology, it is unsurprising that they also influence the response of a living organism to disease, stress, and therapeutics. Therefore, not only do the mechanisms that maintain health and disrupt homeostasis depend on our internal circadian clock, but also the way drugs are perceived and function depends on these physiological rhythms. We present a holistic view of the therapeutic process, discussing components such as disease state, pharmacokinetics, and pharmacodynamics, as well as adverse reactions that are critically affected by circadian rhythms. We outline challenges and opportunities in moving toward personalized medicine approaches that explore and capitalize on circadian rhythms for the benefit of the patient.
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Affiliation(s)
- Yaakov Nahmias
- Center for Bioengineering, School of Computer Science and Engineering, Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Ioannis P Androulakis
- Department of Biomedical Engineering and Department of Chemical & Biochemical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA; .,Department of Surgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, USA
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33
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Yi JS, Díaz NM, D'Souza S, Buhr ED. The molecular clockwork of mammalian cells. Semin Cell Dev Biol 2021; 126:87-96. [PMID: 33810978 DOI: 10.1016/j.semcdb.2021.03.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/20/2022]
Abstract
Most organisms contain self-sustained circadian clocks. These clocks can be synchronized by environmental stimuli, but can also oscillate indefinitely in isolation. In mammals this is true at the molecular level for the majority of cell types that have been examined. A core set of "clock genes" form a transcriptional/translational feedback loop (TTFL) which repeats with a period of approximately 24 h. The exact mechanism of the TTFL differs slightly in various cell types, but all involve similar family members of the core cohort of clock genes. The clock has many outputs which are unique for different tissues. Cells in diverse tissues will convert the timing signals provided by the TTFL into uniquely orchestrated transcriptional oscillations of many clock-controlled genes and cellular processes.
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Affiliation(s)
- Jonathan S Yi
- University of Washington, Dept. of Ophthalmology, 750 Republican St., Seattle, WA 98109, USA
| | - Nicolás M Díaz
- University of Washington, Dept. of Ophthalmology, 750 Republican St., Seattle, WA 98109, USA
| | - Shane D'Souza
- Center for Chronobiology, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA
| | - Ethan D Buhr
- University of Washington, Dept. of Ophthalmology, 750 Republican St., Seattle, WA 98109, USA.
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34
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Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse. J Pharmacokinet Pharmacodyn 2021; 48:361-374. [PMID: 33768484 DOI: 10.1007/s10928-021-09750-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/17/2021] [Indexed: 10/21/2022]
Abstract
A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadian variation at the individual gene level, orchestrates functional responses at the pathway level. Such pathway-based "meta-data" analysis enables the rational integration and comparison across platforms and/or experimental designs evaluating emergent dynamics, as opposed to comparisons of individual elements. One of our key findings is that when considering the dynamics at the pathway level, a complex behavior emerges. Our work proposes that tissues tend to coordinate gene's circadian expression in a way that optimizes tissue-specific pathway activity, depending of each tissue's broader role in homeostasis.
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35
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Yan J, Kim YJ, Somers DE. Post-Translational Mechanisms of Plant Circadian Regulation. Genes (Basel) 2021; 12:325. [PMID: 33668215 PMCID: PMC7995963 DOI: 10.3390/genes12030325] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022] Open
Abstract
The molecular components of the circadian system possess the interesting feature of acting together to create a self-sustaining oscillator, while at the same time acting individually, and in complexes, to confer phase-specific circadian control over a wide range of physiological and developmental outputs. This means that many circadian oscillator proteins are simultaneously also part of the circadian output pathway. Most studies have focused on transcriptional control of circadian rhythms, but work in plants and metazoans has shown the importance of post-transcriptional and post-translational processes within the circadian system. Here we highlight recent work describing post-translational mechanisms that impact both the function of the oscillator and the clock-controlled outputs.
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Affiliation(s)
| | | | - David E. Somers
- Department of Molecular Genetics, The Ohio State University; Columbus, OH 43210, USA; (J.Y.); (Y.J.K.)
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36
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Androulakis IP. Circadian rhythms and the HPA axis: A systems view. WIREs Mech Dis 2021; 13:e1518. [PMID: 33438348 DOI: 10.1002/wsbm.1518] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 11/20/2020] [Accepted: 11/30/2020] [Indexed: 12/26/2022]
Abstract
The circadian timing system comprises a network of time-keeping clocks distributed across a living host whose responsibility is to allocate resources and distribute functions temporally to optimize fitness. The molecular structures generating these rhythms have evolved to accommodate the rotation of the earth in an attempt to primarily match the light/dark periods during the 24-hr day. To maintain synchrony of timing across and within tissues, information from the central clock, located in the suprachiasmatic nucleus, is conveyed using systemic signals. Leading among those signals are endocrine hormones, and while the hypothalamic-pituitary-adrenal axis through the release of glucocorticoids is a major pacesetter. Interestingly, the fundamental units at the molecular and physiological scales that generate local and systemic signals share critical structural properties. These properties enable time-keeping systems to generate rhythmic signals and allow them to adopt specific properties as they interact with each other and the external environment. The purpose of this review is to provide a broad overview of these structures, discuss their functional characteristics, and describe some of their fundamental properties as these related to health and disease. This article is categorized under: Immune System Diseases > Computational Models Immune System Diseases > Biomedical Engineering.
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Affiliation(s)
- Ioannis P Androulakis
- Biomedical Engineering Department, Chemical & Biochemical Engineering Department, Rutgers University, New Brunswick, New Jersey.,Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
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37
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Tinarelli F, Ivanova E, Colombi I, Barini E, Balzani E, Garcia CG, Gasparini L, Chiappalone M, Kelsey G, Tucci V. Cell-cell coupling and DNA methylation abnormal phenotypes in the after-hours mice. Epigenetics Chromatin 2021; 14:1. [PMID: 33407878 PMCID: PMC7789812 DOI: 10.1186/s13072-020-00373-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 11/13/2020] [Indexed: 11/10/2022] Open
Abstract
Background DNA methylation has emerged as an important epigenetic regulator of brain processes, including circadian rhythms. However, how DNA methylation intervenes between environmental signals, such as light entrainment, and the transcriptional and translational molecular mechanisms of the cellular clock is currently unknown. Here, we studied the after-hours mice, which have a point mutation in the Fbxl3 gene and a lengthened circadian period. Methods In this study, we used a combination of in vivo, ex vivo and in vitro approaches. We measured retinal responses in Afh animals and we have run reduced representation bisulphite sequencing (RRBS), pyrosequencing and gene expression analysis in a variety of brain tissues ex vivo. In vitro, we used primary neuronal cultures combined to micro electrode array (MEA) technology and gene expression. Results We observed functional impairments in mutant neuronal networks, and a reduction in the retinal responses to light-dependent stimuli. We detected abnormalities in the expression of photoreceptive melanopsin (OPN4). Furthermore, we identified alterations in the DNA methylation pathways throughout the retinohypothalamic tract terminals and links between the transcription factor Rev-Erbα and Fbxl3. Conclusions The results of this study, primarily represent a contribution towards an understanding of electrophysiological and molecular phenotypic responses to external stimuli in the Afh model. Moreover, as DNA methylation has recently emerged as a new regulator of neuronal networks with important consequences for circadian behaviour, we discuss the impact of the Afh mutation on the epigenetic landscape of circadian biology.
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Affiliation(s)
- Federico Tinarelli
- Genetics and Epigenetics of Behaviour (GEB) Laboratory, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.,BioMed X Innovation Center, Im Neuenheimer Feld 515, 69120, Heidelberg, Germany
| | - Elena Ivanova
- Epigenetics Programme, The Babraham Institute, Cambridge, UK
| | - Ilaria Colombi
- Neuroscience and Brain Technologies, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.,Brain Development and Disease, NBT, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy
| | - Erica Barini
- Neurodevelopmental and Neurodegenerative Disease Laboratory, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.,AbbVie Deutschland GmbH & Co, Knollstr, 67061, Ludwigshafen, Germany
| | - Edoardo Balzani
- Genetics and Epigenetics of Behaviour (GEB) Laboratory, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.,Center for Neural Science, New York University, New York, NY, 10006, USA
| | - Celina Garcia Garcia
- Genetics and Epigenetics of Behaviour (GEB) Laboratory, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy
| | - Laura Gasparini
- Neurodevelopmental and Neurodegenerative Disease Laboratory, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.,AbbVie Deutschland GmbH & Co, Knollstr, 67061, Ludwigshafen, Germany
| | - Michela Chiappalone
- Neuroscience and Brain Technologies, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.,Rehab Technologies, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy
| | - Gavin Kelsey
- Epigenetics Programme, The Babraham Institute, Cambridge, UK
| | - Valter Tucci
- Genetics and Epigenetics of Behaviour (GEB) Laboratory, Istituto Italiano Di Tecnologia, via Morego, 30, 16163, Genova, Italy.
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38
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Liu JA, Walton JC, DeVries AC, Nelson RJ. Disruptions of Circadian Rhythms and Thrombolytic Therapy During Ischemic Stroke Intervention. Front Neurosci 2021; 15:675732. [PMID: 34177452 PMCID: PMC8222607 DOI: 10.3389/fnins.2021.675732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 05/11/2021] [Indexed: 11/24/2022] Open
Abstract
Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.
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Affiliation(s)
- Jennifer A Liu
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
| | - James C Walton
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
| | - A Courtney DeVries
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States.,Department of Medicine, Division of Oncology/Hematology, West Virginia University, Morgantown, WV, United States.,West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, United States
| | - Randy J Nelson
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
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39
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Cox KH, Takahashi JS. Introduction to the Clock System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1344:3-20. [PMID: 34773223 DOI: 10.1007/978-3-030-81147-1_1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Circadian (24-h) rhythms dictate almost everything we do, setting our clocks for specific times of sleeping and eating, as well as optimal times for many other basic functions. The physiological systems that coordinate circadian rhythms are intricate, but at their core, they all can be distilled down to cell-autonomous rhythms that are then synchronized within and among tissues. At first glance, these cell-autonomous rhythms may seem rather straight-forward, but years of research in the field has shown that they are strikingly complex, responding to many different external signals, often with remarkable tissue-specificity. To understand the cellular clock system, it is important to be familiar with the major players, which consist of pairs of proteins in a triad of transcriptional/translational feedback loops. In this chapter, we will go through each of the core protein pairs one-by-one, summarizing the literature as to their regulation and their broader impacts on circadian gene expression. We will conclude by briefly examining the human genetics literature, as well as providing perspectives on the future of the study of the molecular clock.
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Affiliation(s)
- Kimberly H Cox
- Department of Neuroscience and Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Joseph S Takahashi
- Department of Neuroscience and Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. .,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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40
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Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm. Nutrients 2020; 12:nu12113476. [PMID: 33198317 PMCID: PMC7696073 DOI: 10.3390/nu12113476] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
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41
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Malaguarnera R, Ledda C, Filippello A, Frasca F, Francavilla VC, Ramaci T, Parisi MC, Rapisarda V, Piro S. Thyroid Cancer and Circadian Clock Disruption. Cancers (Basel) 2020; 12:E3109. [PMID: 33114365 PMCID: PMC7690860 DOI: 10.3390/cancers12113109] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/18/2020] [Accepted: 10/23/2020] [Indexed: 12/12/2022] Open
Abstract
Thyroid cancer (TC) represents the most common malignancy of the endocrine system, with an increased incidence across continents attributable to both improvement of diagnostic procedures and environmental factors. Among the modifiable risk factors, insulin resistance might influence the development of TC. A relationship between circadian clock machinery disfunction and TC has recently been proposed. The circadian clock machinery comprises a set of rhythmically expressed genes responsible for circadian rhythms. Perturbation of this system contributes to the development of pathological states such as cancer. Several clock genes have been found deregulated upon thyroid nodule malignant transformation. The molecular mechanisms linking circadian clock disruption and TC are still unknown but could include insulin resistance. Circadian misalignment occurring during shift work, jet lag, high fat food intake, is associated with increased insulin resistance. This metabolic alteration, in turn, is associated with a well-known risk factor for TC i.e., hyperthyrotropinemia, which could also be induced by sleep disturbances. In this review, we describe the mechanisms controlling the circadian clock function and its involvement in the cell cycle, stemness and cancer. Moreover, we discuss the evidence supporting the link between circadian clockwork disruption and TC development/progression, highlighting its potential implications for TC prevention, diagnosis and therapy.
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Affiliation(s)
- Roberta Malaguarnera
- School of Human and Social Sciences, “Kore” University of Enna, 94100 Enna, Italy; (R.M.); (V.C.F.); (T.R.); (M.C.P.)
| | - Caterina Ledda
- Department of Clinical and Experimental Medicine, Occupational Medicine, University of Catania, 95100 Catania, Italy;
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (A.F.); (S.P.)
| | - Francesco Frasca
- Endocrinology Unit, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy;
| | - Vincenzo Cristian Francavilla
- School of Human and Social Sciences, “Kore” University of Enna, 94100 Enna, Italy; (R.M.); (V.C.F.); (T.R.); (M.C.P.)
| | - Tiziana Ramaci
- School of Human and Social Sciences, “Kore” University of Enna, 94100 Enna, Italy; (R.M.); (V.C.F.); (T.R.); (M.C.P.)
| | - Maria Chiara Parisi
- School of Human and Social Sciences, “Kore” University of Enna, 94100 Enna, Italy; (R.M.); (V.C.F.); (T.R.); (M.C.P.)
| | - Venerando Rapisarda
- Department of Clinical and Experimental Medicine, Occupational Medicine, University of Catania, 95100 Catania, Italy;
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (A.F.); (S.P.)
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42
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Masri S, Nakahata Y, Eckel-Mahan K. Paolo Sassone-Corsi. J Biol Rhythms 2020. [DOI: 10.1177/0748730420962657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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43
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Srikanta SB, Cermakian N. To Ub or not to Ub: Regulation of circadian clocks by ubiquitination and deubiquitination. J Neurochem 2020; 157:11-30. [PMID: 32717140 DOI: 10.1111/jnc.15132] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 12/28/2022]
Abstract
Circadian clocks are internal timing systems that enable organisms to adjust their behavioral and physiological rhythms to the daily changes of their environment. These clocks generate self-sustained oscillations at the cellular, tissue, and behavioral level. The rhythm-generating mechanism is based on a gene expression network with a delayed negative feedback loop that causes the transcripts to oscillate with a period of approximately 24 hr. This oscillatory nature of the proteins involved in this network necessitates that they are intrinsically unstable, with a short half-life. Hence, post-translational modifications (PTMs) are important to precisely time the presence, absence, and interactions of these proteins at appropriate times of the day. Ubiquitination and deubiquitination are counter-balancing PTMs which play a key role in this regulatory process. In this review, we take a comprehensive look at the roles played by the processes of ubiquitination and deubiquitination in the clock machinery of the most commonly studied eukaryotic models of the circadian clock: plants, fungi, fruit flies, and mammals. We present the effects exerted by ubiquitinating and deubiquitinating enzymes on the stability, but also the activity, localization, and interactions of clock proteins. Overall, these PTMs have key roles in regulating not only the pace of the circadian clocks but also their response to external cues and their control of cellular functions.
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Affiliation(s)
- Shashank Bangalore Srikanta
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada.,Laboratory of Molecular Chronobiology, Douglas Research Centre, Montréal, QC, Canada
| | - Nicolas Cermakian
- Laboratory of Molecular Chronobiology, Douglas Research Centre, Montréal, QC, Canada.,Department of Psychiatry, McGill University, Montréal, QC, Canada
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44
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Crosby P, Partch CL. New insights into non-transcriptional regulation of mammalian core clock proteins. J Cell Sci 2020; 133:133/18/jcs241174. [PMID: 32934011 DOI: 10.1242/jcs.241174] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Mammalian circadian rhythms drive ∼24 h periodicity in a wide range of cellular processes, temporally coordinating physiology and behaviour within an organism, and synchronising this with the external day-night cycle. The canonical model for this timekeeping consists of a delayed negative-feedback loop, containing transcriptional activator complex CLOCK-BMAL1 (BMAL1 is also known as ARNTL) and repressors period 1, 2 and 3 (PER1, PER2 and PER3) and cryptochrome 1 and 2 (CRY1 and CRY2), along with a number of accessory factors. Although the broad strokes of this system are defined, the exact molecular mechanisms by which these proteins generate a self-sustained rhythm with such periodicity and fidelity remains a topic of much research. Recent studies have identified prominent roles for a number of crucial post-transcriptional, translational and, particularly, post-translational events within the mammalian circadian oscillator, providing an increasingly complex understanding of the activities and interactions of the core clock proteins. In this Review, we highlight such contemporary work on non-transcriptional events and set it within our current understanding of cellular circadian timekeeping.
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Affiliation(s)
- Priya Crosby
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA
| | - Carrie L Partch
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA
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45
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Finger AM, Dibner C, Kramer A. Coupled network of the circadian clocks: a driving force of rhythmic physiology. FEBS Lett 2020; 594:2734-2769. [PMID: 32750151 DOI: 10.1002/1873-3468.13898] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/06/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022]
Abstract
The circadian system is composed of coupled endogenous oscillators that allow living beings, including humans, to anticipate and adapt to daily changes in their environment. In mammals, circadian clocks form a hierarchically organized network with a 'master clock' located in the suprachiasmatic nucleus of the hypothalamus, which ensures entrainment of subsidiary oscillators to environmental cycles. Robust rhythmicity of body clocks is indispensable for temporally coordinating organ functions, and the disruption or misalignment of circadian rhythms caused for instance by modern lifestyle is strongly associated with various widespread diseases. This review aims to provide a comprehensive overview of our current knowledge about the molecular architecture and system-level organization of mammalian circadian oscillators. Furthermore, we discuss the regulatory roles of peripheral clocks for cell and organ physiology and their implication in the temporal coordination of metabolism in human health and disease. Finally, we summarize methods for assessing circadian rhythmicity in humans.
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Affiliation(s)
- Anna-Marie Finger
- Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Charna Dibner
- Division of Endocrinology, Diabetes, Nutrition, and Patient Education, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
| | - Achim Kramer
- Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
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46
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Lu R, Dong Y, Li JD. Necdin regulates BMAL1 stability and circadian clock through SGT1-HSP90 chaperone machinery. Nucleic Acids Res 2020; 48:7944-7957. [PMID: 32667666 PMCID: PMC7430654 DOI: 10.1093/nar/gkaa601] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 07/02/2020] [Accepted: 07/07/2020] [Indexed: 12/13/2022] Open
Abstract
Circadian clocks are endogenous oscillators that control ∼24-hour physiology and behaviors in virtually all organisms. The circadian oscillator comprises interconnected transcriptional and translational feedback loops, but also requires finely coordinated protein homeostasis including protein degradation and maturation. However, the mechanisms underlying the mammalian clock protein maturation is largely unknown. In this study, we demonstrate that necdin, one of the Prader-Willi syndrome (PWS)-causative genes, is highly expressed in the suprachiasmatic nuclei (SCN), the pacemaker of circadian clocks in mammals. Mice deficient in necdin show abnormal behaviors during an 8-hour advance jet-lag paradigm and disrupted clock gene expression in the liver. By using yeast two hybrid screening, we identified BMAL1, the core component of the circadian clock, and co-chaperone SGT1 as two necdin-interactive proteins. BMAL1 and SGT1 associated with the N-terminal and C-terminal fragments of necdin, respectively. Mechanistically, necdin enables SGT1-HSP90 chaperone machinery to stabilize BMAL1. Depletion of necdin or SGT1/HSP90 leads to degradation of BMAL1 through the ubiquitin-proteasome system, resulting in alterations in both clock gene expression and circadian rhythms. Taken together, our data identify the PWS-associated protein necdin as a novel regulator of the circadian clock, and further emphasize the critical roles of chaperone machinery in circadian clock regulation.
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Affiliation(s)
- Renbin Lu
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P. R. China
- Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P. R. China
| | - Yufan Dong
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P. R. China
| | - Jia-Da Li
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P. R. China
- Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P. R. China
- Hunan Key Laboratory of Medical Genetics, Changsha 410078, Hunan, P. R. China
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47
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Jobanputra AM, Scharf MT, Androulakis IP, Sunderram J. Circadian Disruption in Critical Illness. Front Neurol 2020; 11:820. [PMID: 32849248 PMCID: PMC7431488 DOI: 10.3389/fneur.2020.00820] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
Circadian rhythms play a vital role in metabolic, hormonal, and immunologic function and are often disrupted in patients in the ICU. Circadian rhythms modulate the molecular machinery that responds to injury and illness which can impact recovery. Potential factors contributing to the alteration in circadian rhythmicity in intensive care unit (ICU) patients include abnormal lighting, noise, altered feeding schedules, extensive patient care interactions and medications. These alterations in circadian rhythms in ICU patients may affect outcomes and therefore, normalization of circadian rhythmicity in critically ill patients may be an important part of ICU care.
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Affiliation(s)
- Aesha M. Jobanputra
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
| | - Matthew T. Scharf
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
- Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
| | - Ioannis P. Androulakis
- Biomedical Engineering Department, Rutgers University, Piscataway, NJ, United States
- Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ, United States
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
| | - Jag Sunderram
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
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48
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Cervantes M, Forné I, Ranjit S, Gratton E, Imhof A, Sassone-Corsi P. BMAL1 Associates with NOP58 in the Nucleolus and Contributes to Pre-rRNA Processing. iScience 2020; 23:101151. [PMID: 32450515 PMCID: PMC7256328 DOI: 10.1016/j.isci.2020.101151] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/30/2020] [Accepted: 05/05/2020] [Indexed: 12/24/2022] Open
Abstract
The transcription factor BMAL1 is a core element of the circadian clock that contributes to cyclic control of genes transcribed by RNA polymerase II. By using biochemical cellular fractionation and immunofluorescence analyses we reveal a previously uncharacterized nucleolar localization for BMAL1. We used an unbiased approach to determine the BMAL1 interactome by mass spectrometry and identified NOP58 as a prominent nucleolar interactor. NOP58, a core component of the box C/D small nucleolar ribonucleoprotein complex, associates with Snord118 to control specific pre-ribosomal RNA (pre-rRNA) processing steps. These results suggest a non-canonical role of BMAL1 in ribosomal RNA regulation. Indeed, we show that BMAL1 controls NOP58-associated Snord118 nucleolar levels and cleavage of unique pre-rRNA intermediates. Our findings identify an unsuspected function of BMAL1 in the nucleolus that appears distinct from its canonical role in the circadian clock system.
BMAL1 displays a circadian-independent localization in the nucleolus Bmal1-deficient cells show altered nucleolar morphology Interactome proteomics reveals that BMAL1 associates with nucleolar proteins BMAL1 appears to play a non-canonical, non-circadian role in pre-rRNA processing
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Affiliation(s)
- Marlene Cervantes
- Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Ignasi Forné
- Protein Analysis Unit, Biomedical Center, Ludwig Maximilian University of Munich, Munich 80539, Germany
| | - Suman Ranjit
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
| | - Enrico Gratton
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
| | - Axel Imhof
- Protein Analysis Unit, Biomedical Center, Ludwig Maximilian University of Munich, Munich 80539, Germany
| | - Paolo Sassone-Corsi
- Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
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49
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Partch CL. Orchestration of Circadian Timing by Macromolecular Protein Assemblies. J Mol Biol 2020; 432:3426-3448. [DOI: 10.1016/j.jmb.2019.12.046] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 12/13/2022]
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50
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Hudec M, Dankova P, Solc R, Bettazova N, Cerna M. Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus. Int J Mol Sci 2020; 21:E3005. [PMID: 32344535 PMCID: PMC7215839 DOI: 10.3390/ijms21083005] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/14/2020] [Accepted: 04/21/2020] [Indexed: 12/11/2022] Open
Abstract
This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the external environment. These loops are affected by genetic and epigenetic factors. Genetic factors include polymorphisms and mutations of circadian genes. The expression of circadian genes is regulated by epigenetic mechanisms that change from prenatal development to old age. Epigenetic modifications are influenced by the external environment. Most of these modifications are affected by our own life style. Irregular circadian rhythm and low quality of sleep have been shown to increase the risk of developing T2DM and other metabolic disorders. Here, we attempt to provide a wide description of mutual relationships between epigenetic regulation, circadian rhythm, aging process and highlight new evidences that show possible therapeutic advance in the field of chrono-medicine which will be more important in the upcoming years.
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Affiliation(s)
- Michael Hudec
- Department of Medical Genetics, Third Faculty of Medicine, Charles University; Ruská 87, 100 00 Prague, Czech Republic; (N.B.); (M.C.)
| | - Pavlina Dankova
- Department of Anthropology and Human Genetics, Faculty of Science, Charles University; Viničná 7, 128 00 Prague, Czech Republic; (P.D.); (R.S.)
| | - Roman Solc
- Department of Anthropology and Human Genetics, Faculty of Science, Charles University; Viničná 7, 128 00 Prague, Czech Republic; (P.D.); (R.S.)
| | - Nardjas Bettazova
- Department of Medical Genetics, Third Faculty of Medicine, Charles University; Ruská 87, 100 00 Prague, Czech Republic; (N.B.); (M.C.)
| | - Marie Cerna
- Department of Medical Genetics, Third Faculty of Medicine, Charles University; Ruská 87, 100 00 Prague, Czech Republic; (N.B.); (M.C.)
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