|
1
|
Akinborewa O, Quattrocelli M. Glucocorticoid receptor epigenetic activity in the heart. Epigenetics 2025; 20:2468113. [PMID: 40007064 PMCID: PMC11866966 DOI: 10.1080/15592294.2025.2468113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/23/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
The glucocorticoid receptor (GR) is a critical nuclear receptor that regulates gene expression in diverse tissues, including the heart, where it plays a key role in maintaining cardiovascular health. GR signaling influences essential processes within cardiomyocytes, including hypertrophy, calcium handling, and metabolic balance, all of which are vital for proper cardiac function. Dysregulation of GR activity has been implicated in various cardiovascular diseases (CVDs), highlighting the potential of GR as a therapeutic target. Remarkably, recent insights into GR's epigenetic regulation and its interaction with circadian rhythms reveal opportunities to optimize therapeutic strategies by aligning glucocorticoid administration with circadian timing. In this review, we provide an overview of the glucocorticoid receptor's role in cardiac physiology, detailing its genomic and non-genomic pathways, interactions with epigenetic and circadian regulatory mechanisms, and implications for cardiovascular disease. By dissecting these molecular interactions, this review outlines the potential of epigenetically informed and circadian-timed interventions that could change the current paradigms of CVD treatments in favor of precise and effective therapies.
Collapse
Affiliation(s)
- Olukunle Akinborewa
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Mattia Quattrocelli
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| |
Collapse
|
|
2
|
Stewart D, Albrecht U. Beyond vision: effects of light on the circadian clock and mood-related behaviours. NPJ BIOLOGICAL TIMING AND SLEEP 2025; 2:12. [PMID: 40092590 PMCID: PMC11906358 DOI: 10.1038/s44323-025-00029-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 02/17/2025] [Indexed: 03/19/2025]
Abstract
Light is a crucial environmental factor that influences various aspects of life, including physiological and psychological processes. While light is well-known for its role in enabling humans and other animals to perceive their surroundings, its influence extends beyond vision. Importantly, light affects our internal time-keeping system, the circadian clock, which regulates daily rhythms of biochemical and physiological processes, ultimately impacting mood and behaviour. The 24-h availability of light can have profound effects on our well-being, both physically and mentally, as seen in cases of jet lag and shift work. This review summarizes the intricate relationships between light, the circadian clock, and mood-related behaviours, exploring the underlying mechanisms and its implications for health.
Collapse
Affiliation(s)
- Dean Stewart
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | - Urs Albrecht
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| |
Collapse
|
|
3
|
Silva Angulo F, Joseph CV, Delval L, Deruyter L, Heumel S, Bicharel M, Rodrigues PB, Sencio V, Bourguignon T, Machado MG, Fourcot M, Delhaye S, Salomé-Desnoulez S, Valet P, Adnot S, Wolowczuk I, Sirard JC, Pichavant M, Staels B, Haas JT, Gref R, Vandel J, Machelart A, Duez H, Pourcet B, Trottein F. Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice. Cell Rep 2025; 44:115273. [PMID: 39908141 DOI: 10.1016/j.celrep.2025.115273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 10/08/2024] [Accepted: 01/15/2025] [Indexed: 02/07/2025] Open
Abstract
Circadian rhythms control the diurnal nature of many physiological, metabolic, and immune processes. We hypothesized that age-related impairments in circadian rhythms are associated with high susceptibility to bacterial respiratory tract infections. Our data show that the time-of-day difference in the control of Streptococcus pneumoniae infection is altered in elderly mice. A lung circadian transcriptome analysis revealed that aging alters the daily oscillations in the expression of a specific set of genes and that some pathways that are rhythmic in young-adult mice are non-rhythmic or time shifted in elderly mice. In particular, the circadian expression of the clock component Rev-erb-α and apelin/apelin receptor was altered in elderly mice. In young-adult mice, we discovered an interaction between Rev-erb-α and the apelinergic axis that controls host defenses against S. pneumoniae via alveolar macrophages. Pharmacological repression of Rev-erb-α in elderly mice resulted in greater resistance to pneumococcal infection. These data suggest the causative role of age-associated impairments in circadian rhythms on respiratory infections and have clinical relevance.
Collapse
MESH Headings
- Animals
- Macrophages, Alveolar/metabolism
- Macrophages, Alveolar/microbiology
- Macrophages, Alveolar/drug effects
- Macrophages, Alveolar/immunology
- Nuclear Receptor Subfamily 1, Group D, Member 1/antagonists & inhibitors
- Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism
- Nuclear Receptor Subfamily 1, Group D, Member 1/genetics
- Circadian Rhythm/genetics
- Pneumococcal Infections/prevention & control
- Pneumococcal Infections/immunology
- Pneumococcal Infections/metabolism
- Pneumococcal Infections/microbiology
- Pneumococcal Infections/genetics
- Mice
- Streptococcus pneumoniae
- Aging
- Mice, Inbred C57BL
- Male
- Lung/metabolism
- Lung/microbiology
Collapse
Affiliation(s)
- Fabiola Silva Angulo
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Claudine Vanessa Joseph
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Lou Delval
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Lucie Deruyter
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Séverine Heumel
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Marie Bicharel
- University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, 59000 Lille, France
| | - Patricia Brito Rodrigues
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Valentin Sencio
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Tom Bourguignon
- University Paris Saclay, CNRS, UMR 8214 - Institute of Molecular Sciences, 91400 Orsay, France
| | - Marina Gomes Machado
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Marie Fourcot
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, 59000 Lille, France
| | - Stéphane Delhaye
- University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, 59000 Lille, France
| | - Sophie Salomé-Desnoulez
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, 59000 Lille, France
| | - Philippe Valet
- University Paul Sabatier, University Toulouse, INSERM, CNRS, U1301 - UMR 5070 - Institut RESTORE, 31000 Toulouse, France
| | - Serge Adnot
- University Paris-Est Créteil, INSERM, U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France
| | - Isabelle Wolowczuk
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Jean-Claude Sirard
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Muriel Pichavant
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Bart Staels
- University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, 59000 Lille, France
| | - Joel T Haas
- University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, 59000 Lille, France
| | - Ruxandra Gref
- University Paris Saclay, CNRS, UMR 8214 - Institute of Molecular Sciences, 91400 Orsay, France
| | - Jimmy Vandel
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, 59000 Lille, France
| | - Arnaud Machelart
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Hélène Duez
- University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, 59000 Lille, France.
| | - Benoit Pourcet
- University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, 59000 Lille, France.
| | - François Trottein
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France.
| |
Collapse
|
|
4
|
Helm B, Liedvogel M. Avian migration clocks in a changing world. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2024; 210:691-716. [PMID: 38305877 PMCID: PMC11226503 DOI: 10.1007/s00359-023-01688-w] [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: 05/16/2023] [Revised: 12/13/2023] [Accepted: 12/22/2023] [Indexed: 02/03/2024]
Abstract
Avian long-distance migration requires refined programming to orchestrate the birds' movements on annual temporal and continental spatial scales. Programming is particularly important as long-distance movements typically anticipate future environmental conditions. Hence, migration has long been of particular interest in chronobiology. Captivity studies using a proxy, the shift to nocturnality during migration seasons (i.e., migratory restlessness), have revealed circannual and circadian regulation, as well as an innate sense of direction. Thanks to rapid development of tracking technology, detailed information from free-flying birds, including annual-cycle data and actograms, now allows relating this mechanistic background to behaviour in the wild. Likewise, genomic approaches begin to unravel the many physiological pathways that contribute to migration. Despite these advances, it is still unclear how migration programmes are integrated with specific environmental conditions experienced during the journey. Such knowledge is imminently important as temporal environments undergo rapid anthropogenic modification. Migratory birds as a group are not dealing well with the changes, yet some species show remarkable adjustments at behavioural and genetic levels. Integrated research programmes and interdisciplinary collaborations are needed to understand the range of responses of migratory birds to environmental change, and more broadly, the functioning of timing programmes under natural conditions.
Collapse
Affiliation(s)
- Barbara Helm
- Swiss Ornithological Institute, Bird Migration Unit, Seerose 1, CH-6204, Sempach, Schweiz.
| | - Miriam Liedvogel
- Institute of Avian Research, An Der Vogelwarte 21, 26386, Wilhelmshaven, Germany
| |
Collapse
|
|
5
|
Maidstone R, Rutter MK, Marjot T, Ray DW, Baxter M. Shift work and evening chronotype are associated with hepatic fat fraction and non-alcoholic fatty liver disease in 282,303 UK biobank participants. Endocr Connect 2024; 13:e230472. [PMID: 38055788 PMCID: PMC10831536 DOI: 10.1530/ec-23-0472] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 12/06/2023] [Indexed: 12/08/2023]
Abstract
Background and aims Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease worldwide. Modern lifestyles have been linked to this rise in prevalence with changes in rhythmic human behaviour emerging as a possible mechanism. We investigated how shift working patterns and chronotype were associated with hepatic fat fraction and NAFLD in 282,303 UK Biobank participants. Methods We stratified participants into day, irregular-shift, and permanent night-shift workers. We then utilised multiple methods of disease identification including (i) Dallas steatosis index (DSI), (ii) ICD10 codes, and (iii) hepatic proton density fat fraction (PDFF) and examined how shift work exposure impacted these variables. We further assessed the relationship of baseline chronotype with liver phenotypes using these same outcome measures. Results Compared to day workers, irregular-shift workers were more likely to have a high DSI (OR 1.29 (1.2-1.4)) after adjusting for major covariates with some attenuation after additional adjustment for BMI (OR 1.12 (1.03-1.22)). Likelihood of high DSI was also increased in permanent night-shift workers (OR 1.08 (0.9-1.29)) in the fully adjusted model. Mediator analysis revealed that BMI was a significant mediator of the shift work effect. Compared to participants with intermediate chronotype, those with extreme late chronotype had a higher likelihood of high DSI defined NAFLD (OR 1.45 (1.34-1.56)) and a higher likelihood of NAFLD/NASH by ICD10 code (OR 1.23 (1.09-1.39)). Hepatic PDFF was elevated in irregular shift workers, but not permanent night-shift workers. Conclusions Irregular-shift work and extreme late chronotype are associated with pathological liver fat accumulation, suggesting circadian misalignment may have an underlying pathogenic role. These findings have implications for health interventions to mitigate the detrimental effect of shift work.
Collapse
Affiliation(s)
- Robert Maidstone
- Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Martin K Rutter
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK
| | - Thomas Marjot
- Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
- Oxford Liver Unit, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, UK
| | - David W Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
- NIHR Oxford Health Biomedical Research Centre, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
| | - Matthew Baxter
- Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
- NIHR Oxford Health Biomedical Research Centre, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
| |
Collapse
|
|
6
|
Bolshette N, Ibrahim H, Reinke H, Asher G. Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology. Nat Rev Gastroenterol Hepatol 2023; 20:695-707. [PMID: 37291279 DOI: 10.1038/s41575-023-00792-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2023] [Indexed: 06/10/2023]
Abstract
A wide variety of liver functions are regulated daily by the liver circadian clock and via systemic circadian control by other organs and cells within the gastrointestinal tract as well as the microbiome and immune cells. Disruption of the circadian system, as occurs during jetlag, shift work or an unhealthy lifestyle, is implicated in several liver-related pathologies, ranging from metabolic diseases such as obesity, type 2 diabetes mellitus and nonalcoholic fatty liver disease to liver malignancies such as hepatocellular carcinoma. In this Review, we cover the molecular, cellular and organismal aspects of various liver pathologies from a circadian viewpoint, and in particular how circadian dysregulation has a role in the development and progression of these diseases. Finally, we discuss therapeutic and lifestyle interventions that carry health benefits through support of a functional circadian clock that acts in synchrony with the environment.
Collapse
Affiliation(s)
- Nityanand Bolshette
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Hussam Ibrahim
- University of Düsseldorf, Medical Faculty, Institute of Clinical Chemistry and Laboratory Diagnostics, Düsseldorf, Germany
| | - Hans Reinke
- University of Düsseldorf, Medical Faculty, Institute of Clinical Chemistry and Laboratory Diagnostics, Düsseldorf, Germany.
| | - Gad Asher
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
| |
Collapse
|
|
7
|
Meijer OC, Kooijman S, Kroon J, Winter EM. The importance of the circadian trough in glucocorticoid signaling: a variation on B-flat. Stress 2023; 26:2275210. [PMID: 37874158 DOI: 10.1080/10253890.2023.2275210] [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: 06/24/2023] [Accepted: 09/28/2023] [Indexed: 10/25/2023] Open
Abstract
Glucocorticoid hormones are essential for health, but overexposure may lead to many detrimental effects, including metabolic, psychiatric, and bone disease. These effects may not only be due to increased overall exposure to glucocorticoids, but also to elevated hormone levels at the time of the physiological circadian trough of glucocorticoid levels. The late Mary Dallman developed a model that allows the differentiation between the effects of overall 24-hour glucocorticoid overexposure and the effects of a lack of circadian rhythmicity. For this, she continuously treated rats with a low dose of corticosterone (or "B"), which leads to a constant hormone level, without 24-hour overexposure using subcutaneously implanted pellets. The data from this "B-flat" model suggest that even modest elevations of glucocorticoid signaling during the time of the normal circadian trough of hormone secretion are a substantial contributor to the negative effects of glucocorticoids on health.
Collapse
Affiliation(s)
- Onno C Meijer
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Sander Kooijman
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Kroon
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Elizabeth M Winter
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
8
|
Zheng G, Pang S, Wang J, Wang F, Wang Q, Yang L, Ji M, Xie D, Zhu S, Chen Y, Zhou Y, Higgins GA, Wiley JW, Hou X, Lin R. Glucocorticoid receptor-mediated Nr1d1 chromatin circadian misalignment in stress-induced irritable bowel syndrome. iScience 2023; 26:107137. [PMID: 37404374 PMCID: PMC10316663 DOI: 10.1016/j.isci.2023.107137] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/28/2023] [Accepted: 06/12/2023] [Indexed: 07/06/2023] Open
Abstract
Stress-elevated glucocorticoids cause circadian disturbances and gut-brain axis (GBA) disorders, including irritable bowel syndrome (IBS). We hypothesized that the glucocorticoid receptor (GR/NR3C1) might cause chromatin circadian misalignment in the colon epithelium. We observed significantly decreased core circadian gene Nr1d1 in water avoidance stressed (WAS) BALB/c colon epithelium, like in IBS patients. WAS decreased GR binding at the Nr1d1 promoter E-box (enhancer box), and GR could suppress Nr1d1 via this site. Stress also altered GR binding at the E-box sites along the Ikzf3-Nr1d1 chromatin and remodeled circadian chromatin 3D structures, including Ikzf3-Nr1d1 super-enhancer, Dbp, and Npas2. Intestinal deletion of Nr3c1 specifically abolished these stress-induced transcriptional alternations relevant to IBS phenotypes in BALB/c mice. GR mediated Ikzf3-Nr1d1 chromatin disease related circadian misalignment in stress-induced IBS animal model. This animal model dataset suggests that regulatory SNPs of human IKZF3-NR1D1 transcription through conserved chromatin looping have translational potential based on the GR-mediated circadian-stress crosstalk.
Collapse
Affiliation(s)
- Gen Zheng
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Suya Pang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Junbao Wang
- Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China
| | - Fangyu Wang
- Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China
| | - Qi Wang
- The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Lili Yang
- Central Laboratory of Yan’an Hospital Affiliated to Kunming Medical University, Kunming Medical University, Kunming 650500, China
| | - Mengdie Ji
- The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Dejian Xie
- Beijing Research Center, Wuhan Frasergen Bioinformatics Co., Ltd, Beijing 100081, China
| | - Shengtao Zhu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yang Chen
- The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Yan Zhou
- Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China
| | - Gerald A. Higgins
- Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor 48109, MI, USA
| | - John W. Wiley
- Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor 48109, MI, USA
| | - Xiaohua Hou
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| |
Collapse
|
|
9
|
Deploey N, Van Moortel L, Rogatsky I, Peelman F, De Bosscher K. The Biologist's Guide to the Glucocorticoid Receptor's Structure. Cells 2023; 12:1636. [PMID: 37371105 PMCID: PMC10297449 DOI: 10.3390/cells12121636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt inflammation and kill off cancer cells, thus explaining the widespread use of glucocorticoids in the clinic. However, side effects and therapy resistance limit GR's therapeutic potential, emphasizing the importance of resolving all of GR's context-specific action mechanisms. Fortunately, the understanding of GR structure, conformation, and stoichiometry in the different GR-controlled biological pathways is now gradually increasing. This information will be crucial to close knowledge gaps on GR function. In this review, we focus on the various domains and mechanisms of action of GR, all from a structural perspective.
Collapse
Affiliation(s)
- Nick Deploey
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, 9052 Ghent, Belgium
| | - Laura Van Moortel
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, 9052 Ghent, Belgium
| | - Inez Rogatsky
- Hospital for Special Surgery Research Institute, The David Z. Rosensweig Genomics Center, New York, NY 10021, USA;
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
| | - Frank Peelman
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Karolien De Bosscher
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, 9052 Ghent, Belgium
| |
Collapse
|
|
10
|
Caratti G, Stifel U, Caratti B, Jamil AJM, Chung KJ, Kiehntopf M, Gräler MH, Blüher M, Rauch A, Tuckermann JP. Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance. Nat Commun 2023; 14:2271. [PMID: 37080971 PMCID: PMC10119112 DOI: 10.1038/s41467-023-37831-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 04/01/2023] [Indexed: 04/22/2023] Open
Abstract
Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.
Collapse
Affiliation(s)
- Giorgio Caratti
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX37LE, UK
| | - Ulrich Stifel
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
| | - Bozhena Caratti
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
| | - Ali J M Jamil
- Molecular Endocrinology & Stem Cell Research Unit, Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Kyoung-Jin Chung
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technical University Dresden, Dresden, Germany
| | - Michael Kiehntopf
- SG Sepsis Research Clinic for Anesthesiology and Intensive Care, Jena University Hospital, Jena, Germany
| | - Markus H Gräler
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Center for Molecular Biomedicine (CMB), Jena University Hospital, Jena, Germany
- Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany
| | - Matthias Blüher
- Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany
| | - Alexander Rauch
- Molecular Endocrinology & Stem Cell Research Unit, Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
- Steno Diabetes Center Odense, Odense, Denmark.
| | - Jan P Tuckermann
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
| |
Collapse
|
|
11
|
Weintraub Y, Cohen S, Anafy A, Chapnik N, Tsameret S, Ben-Tov A, Yerushalmy-Feler A, Dotan I, Tauman R, Froy O. Inverse Relationship Between Clock Gene Expression and Inflammatory Markers in Ulcerative Colitis Patients Undergoing Remission. Dig Dis Sci 2023; 68:2454-2462. [PMID: 36745299 DOI: 10.1007/s10620-023-07847-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/24/2023] [Indexed: 02/07/2023]
Abstract
BACKGROUND Changes in the expression of clock genes have been reported in inflammatory bowel disease (IBD) patients. AIMS We aimed to investigate whether reduced inflammation restores clock gene expression to levels of healthy controls. METHODS This was a prospective study. Participants completed questionnaires providing data on demographics, sleeping habits, and disease activity. Anthropometric parameters, C-reactive protein (CRP), and fecal calprotectin (Fcal) levels were collected. Peripheral blood samples were analyzed for clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, PER2) expression. Patients with IBD were separated by diagnosis into ulcerative colitis (UC) and Crohn's disease (CD). Each diagnosis was further divided into active disease and disease under remission. RESULTS Forty-nine patients with IBD and 19 healthy controls completed the study. BMAL1 and PER2 were significantly reduced in active patients with UC compared to patients with UC in remission. BMAL1, PER1, and PER2 were significantly reduced in patients with UC with CRP > 5 mg/dl. PER2, CRY1, and CRY2 were significantly reduced in patients with UC with Fcal > 250 mg/kg. Clock gene expression of patients with UC in remission was comparable to healthy controls. When all patients with IBD were analyzed, an overshoot in CRY1 expression was observed in patients in remission, patients with CRP < 5 mg/dl, and patients with Fcal < 250 mg/kg. CONCLUSION CRP and Fcal are inversely related to clock gene levels in patients with UC. CRY1 may play a role in counteracting the anti-inflammatory processes when remission is induced in patients with IBD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03662646.
Collapse
Affiliation(s)
- Y Weintraub
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - S Cohen
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Sourasky Tel-Aviv Medical Center, Tel Aviv, Israel
| | - A Anafy
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Sourasky Tel-Aviv Medical Center, Tel Aviv, Israel
| | - N Chapnik
- Institute of Biochemistry, Food Science and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel
| | - S Tsameret
- Institute of Biochemistry, Food Science and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel
| | - A Ben-Tov
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Sourasky Tel-Aviv Medical Center, Tel Aviv, Israel
| | - A Yerushalmy-Feler
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Sourasky Tel-Aviv Medical Center, Tel Aviv, Israel
| | - I Dotan
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - R Tauman
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Sleep Disorders Center, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - O Froy
- Institute of Biochemistry, Food Science and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel.
| |
Collapse
|
|
12
|
Zandi M, Shafaati M, Shapshak P, Hashemnia SMR. Monkeypox virus replication underlying circadian rhythm networks. J Neurovirol 2023; 29:1-7. [PMID: 36719593 PMCID: PMC9888333 DOI: 10.1007/s13365-023-01118-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/11/2023] [Accepted: 01/21/2023] [Indexed: 02/01/2023]
Abstract
The mammalian brain has an endogenous central circadian clock that regulates central and peripheral cellular activities. At the molecular level, this day-night cycle induces the expression of upstream and downstream transcription factors that influence the immune system and the severity of viral infections over time. In addition, there are also circadian effects on host tolerance pathways. This stimulates adaptation to normal changes in environmental conditions and requirements (including light and food). These rhythms influence the pharmacokinetics and efficacy of therapeutic drugs and vaccines. The importance of circadian systems in regulating viral infections and the host response to viruses is currently of great importance for clinical management. With the knowledge gained from the COVID-19 pandemic, it is important to address any outbreak of viral infection that could become endemic and to quickly focus research on any knowledge gaps. For example, responses to booster vaccination COVID-19 may have different time-dependent patterns during circadian cycles. There may be a link between reactivation of latently infected viruses and regulation of circadian rhythms. In addition, mammals may show different seasonal antiviral responses in winter and summer. This article discusses the importance of the host circadian clock during monkeypox infection and immune system interactions.
Collapse
Affiliation(s)
- Milad Zandi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| | - Maryam Shafaati
- Department of Microbiology, Faculty Science, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | - Paul Shapshak
- Global Disease Institute, Tampa General Hospital, Division of Infectious Diseases and International Health, Department of Internal Medicine, Morsani College of Medicine, Tampa, FL, USA
| | | |
Collapse
|
|
13
|
Kalita E, Panda M, Prajapati VK. The interplay between circadian clock and viral infections: A molecular perspective. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 137:293-330. [PMID: 37709380 DOI: 10.1016/bs.apcsb.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
The circadian clock influences almost every aspect of mammalian behavioral, physiological and metabolic processes. Being a hierarchical network, the circadian clock is driven by the central clock in the brain and is composed of several peripheral tissue-specific clocks. It orchestrates and synchronizes the daily oscillations of biological processes to the environment. Several pathological events are influenced by time and seasonal variations and as such implicate the clock in pathogenesis mechanisms. In context with viral infections, circadian rhythmicity is closely associated with host susceptibility, disease severity, and pharmacokinetics and efficacies of antivirals and vaccines. Leveraging the circadian molecular mechanism insights has increased our understanding of clock infection biology and proposes new avenues for viral diagnostics and therapeutics. In this chapter, we address the molecular interplay between the circadian clock and viral infections and discuss the importance of chronotherapy as a complementary approach to conventional medicines, emphasizing the significance of virus-clock studies.
Collapse
Affiliation(s)
- Elora Kalita
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, India
| | - Mamta Panda
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India..
| |
Collapse
|
|
14
|
Mortimer T. Getting the clock back on its feet: targeting the circadian clock to treat osteoarthritis. FEBS J 2022; 289:6640-6642. [PMID: 36271686 DOI: 10.1111/febs.16648] [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: 09/08/2022] [Accepted: 10/06/2022] [Indexed: 06/16/2023]
Abstract
Growing evidence suggests that circadian clock dysfunction may contribute to the pathology of osteoarthritis. In this issue, He et al. use in vivo and human-derived osteoarthritis models to demonstrate the therapeutic potential of pharmacologically manipulating components of the cartilage circadian clock. In doing so, the authors provide an important proof-of-principle supporting circadian clock-targeted therapy as a treatment option for osteoarthritis. Comment on: https://doi.org/10.1111/febs.16601.
Collapse
Affiliation(s)
- Thomas Mortimer
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Spain
| |
Collapse
|
|
15
|
Niu Y, Tang S. Circadian clock-mediated nuclear receptors in cancer. J Cell Physiol 2022; 237:4428-4442. [PMID: 36250982 DOI: 10.1002/jcp.30905] [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: 06/07/2022] [Revised: 09/25/2022] [Accepted: 10/03/2022] [Indexed: 11/09/2022]
Abstract
Circadian system coordinates the daily periodicity of physiological and biochemical functions to adapt to environmental changes. Circadian disruption has been identified to increase the risk of cancer and promote cancer progression, but the underlying mechanism remains unclear. And further mechanistic understanding of the crosstalk between clock components and cancer is urgent to achieve clinical anticancer benefits from chronochemotherapy. Recent studies discover that several nuclear receptors regulating circadian clock, also play crucial roles in mediating multiple cancer processes. In this review, we aim to summarize the latest developments of clock-related nuclear receptors in cancer biology and dissect mechanistic insights into how nuclear receptors coordinate with circadian clock to regulate tumorigenesis and cancer treatment. A better understanding of circadian clock-related nuclear receptors in cancer could help prevent tumorigenesis and improve anticancer efficacy.
Collapse
Affiliation(s)
- Ya Niu
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuang Tang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| |
Collapse
|
|
16
|
Zhu B. Logic of the Temporal Compartmentalization of the Hepatic Metabolic Cycle. Physiology (Bethesda) 2022; 37:0. [PMID: 35658626 PMCID: PMC9394779 DOI: 10.1152/physiol.00003.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/05/2022] [Accepted: 05/28/2022] [Indexed: 12/25/2022] Open
Abstract
The mammalian liver must cope with various metabolic and physiological changes that normally recur every day and result primarily from rest-activity and fasting-feeding cycles. In this article, I present evidence supporting a temporal compartmentalization of rhythmic hepatic metabolic processes into four main clusters: regulation of energy homeostasis, maintenance of information integrity, immune response, and genetic information flow. I further review literatures and discuss how both the circadian and the newly discovered 12-h ultradian clock work together to regulate these four temporally separated processes in mouse liver, which, interestingly, is largely uncoupled from the liver zonation regulation.
Collapse
Affiliation(s)
- Bokai Zhu
- Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| |
Collapse
|
|
17
|
Skrlec I, Talapko J. Hepatitis B and circadian rhythm of the liver. World J Gastroenterol 2022; 28:3282-3296. [PMID: 36158265 PMCID: PMC9346465 DOI: 10.3748/wjg.v28.i27.3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm in humans is determined by the central clock located in the hypothalamus's suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus's life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.
Collapse
Affiliation(s)
- Ivana Skrlec
- Department of Biophysics, Biology, and Chemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Jasminka Talapko
- Department of Anatomy Histology, Embryology, Pathology Anatomy and Pathology Histology, Faculty of Dental Medicine and Health, Osijek 31000, Croatia
| |
Collapse
|
|
18
|
Baxter M, Poolman T, Cunningham P, Hunter L, Voronkov M, Kitchen GB, Goosey L, Begley N, Kay D, Hespe A, Maidstone R, Loudon ASI, Ray DW. Circadian clock function does not require the histone methyltransferase MLL3. FASEB J 2022; 36:e22356. [PMID: 35704036 PMCID: PMC9328146 DOI: 10.1096/fj.202200368r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/26/2022] [Accepted: 05/06/2022] [Indexed: 11/11/2022]
Abstract
The circadian clock controls the physiological function of tissues through the regulation of thousands of genes in a cell-type-specific manner. The core cellular circadian clock is a transcription-translation negative feedback loop, which can recruit epigenetic regulators to facilitate temporal control of gene expression. Histone methyltransferase, mixed lineage leukemia gene 3 (MLL3) was reported to be required for the maintenance of circadian oscillations in cultured cells. Here, we test the role of MLL3 in circadian organization in whole animals. Using mice expressing catalytically inactive MLL3, we show that MLL3 methyltransferase activity is in fact not required for circadian oscillations in vitro in a range of tissues, nor for the maintenance of circadian behavioral rhythms in vivo. In contrast to a previous report, loss of MLL3-dependent methylation did not affect the global levels of H3K4 methylation in liver, indicating substantial compensation from other methyltransferases. Furthermore, we found little evidence of genomic repositioning of H3K4me3 marks. We did, however, observe repositioning of H3K4me1 from intronic regions to intergenic regions and gene promoters; however, there were no changes in H3K4me1 mark abundance around core circadian clock genes. Output functions of the circadian clock, such as control of inflammation, were largely intact in MLL3-methyltransferase-deficient mice, although some gene-specific changes were observed, with sexually dimorphic loss of circadian regulation of specific cytokines. Taken together, these observations indicate that MLL3-directed histone methylation is not essential for core circadian clock function; however, it may influence the inflammatory response.
Collapse
Affiliation(s)
- Matthew Baxter
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| | - Toryn Poolman
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| | - Peter Cunningham
- Centre for Biological TimingFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Louise Hunter
- Centre for Biological TimingFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Maria Voronkov
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| | - Gareth B. Kitchen
- Centre for Biological TimingFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Laurence Goosey
- Centre for Biological TimingFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Nicola Begley
- Centre for Biological TimingFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Danielle Kay
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| | - Abby Hespe
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| | - Robert Maidstone
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| | - Andrew S. I. Loudon
- Centre for Biological TimingFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - David W. Ray
- NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
| |
Collapse
|
|
19
|
Portuguez AS, Grbesa I, Tal M, Deitch R, Raz D, Kliker L, Weismann R, Schwartz M, Loza O, Cohen L, Marchenkov-Flam L, Sung MH, Kaplan T, Hakim O. Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression. Nucleic Acids Res 2022; 50:6702-6714. [PMID: 35713523 PMCID: PMC9262608 DOI: 10.1093/nar/gkac488] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 05/18/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.
Collapse
Affiliation(s)
| | | | - Moran Tal
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Rachel Deitch
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Dana Raz
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Limor Kliker
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Ran Weismann
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Michal Schwartz
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Olga Loza
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Leslie Cohen
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Libi Marchenkov-Flam
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Building 206, Ramat-Gan 5290002, Israel
| | - Myong-Hee Sung
- Laboratory of Molecular Biology and Immunology, NIA, National Institutes of Health, Baltimore, MD 21224, USA
| | - Tommy Kaplan
- School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel,Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91121, Israel
| | - Ofir Hakim
- To whom correspondence should be addressed. Tel: +972 3 738 4295; Fax: +972 3 738 4296;
| |
Collapse
|
|
20
|
Goldberg D, Charni-Natan M, Buchshtab N, Bar-Shimon M, Goldstein I. Hormone-controlled cooperative binding of transcription factors drives synergistic induction of fasting-regulated genes. Nucleic Acids Res 2022; 50:5528-5544. [PMID: 35556130 PMCID: PMC9177981 DOI: 10.1093/nar/gkac358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 04/22/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
During fasting, hepatocytes produce glucose in response to hormonal signals. Glucagon and glucocorticoids are principal fasting hormones that cooperate in regulating glucose production via gluconeogenesis. However, how these hormone signals are integrated and interpreted to a biological output is unknown. Here, we use genome-wide profiling of gene expression, enhancer dynamics and transcription factor (TF) binding in primary mouse hepatocytes to uncover the mode of cooperation between glucagon and glucocorticoids. We found that compared to a single treatment with each hormone, a dual treatment directs hepatocytes to a pro-gluconeogenic gene program by synergistically inducing gluconeogenic genes. The cooperative mechanism driving synergistic gene expression is based on ‘assisted loading’ whereby a glucagon-activated TF (cAMP responsive element binding protein; CREB) leads to enhancer activation which facilitates binding of the glucocorticoid receptor (GR) upon glucocorticoid stimulation. Glucagon does not only activate single enhancers but also activates enhancer clusters, thereby assisting the loading of GR also across enhancer units within the cluster. In summary, we show that cells integrate extracellular signals by an enhancer-specific mechanism: one hormone-activated TF activates enhancers, thereby assisting the loading of a TF stimulated by a second hormone, leading to synergistic gene induction and a tailored transcriptional response to fasting.
Collapse
Affiliation(s)
- Dana Goldberg
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. POB 12, Rehovot 7610001, Israel
| | - Meital Charni-Natan
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. POB 12, Rehovot 7610001, Israel
| | - Nufar Buchshtab
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. POB 12, Rehovot 7610001, Israel
| | - Meirav Bar-Shimon
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. POB 12, Rehovot 7610001, Israel
| | - Ido Goldstein
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. POB 12, Rehovot 7610001, Israel
| |
Collapse
|
|
21
|
Hunter AL, Poolman TM, Kim D, Gonzalez FJ, Bechtold DA, Loudon ASI, Iqbal M, Ray DW. HNF4A modulates glucocorticoid action in the liver. Cell Rep 2022; 39:110697. [PMID: 35443180 PMCID: PMC9380254 DOI: 10.1016/j.celrep.2022.110697] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 01/24/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022] Open
Abstract
The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.
Collapse
Affiliation(s)
- A Louise Hunter
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Toryn M Poolman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK
| | - Donghwan Kim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - David A Bechtold
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Andrew S I Loudon
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Mudassar Iqbal
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - David W Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
| |
Collapse
|
|
22
|
Welch RD, Billon C, Losby M, Bedia-Diaz G, Fang Y, Avdagic A, Elgendy B, Burris TP, Griffett K. Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH. Metabolites 2022; 12:238. [PMID: 35323681 PMCID: PMC8953348 DOI: 10.3390/metabo12030238] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities.
Collapse
Affiliation(s)
- Ryan D. Welch
- Biology and Chemistry Department, Blackburn College, Carlinville, IL 62626, USA;
| | - Cyrielle Billon
- Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University in St. Louis, St. Louis, MO 63110, USA; (C.B.); (G.B.-D.); (Y.F.); (A.A.); (B.E.)
| | - McKenna Losby
- Biochemistry, Biophysics and Structural Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA;
| | - Gonzalo Bedia-Diaz
- Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University in St. Louis, St. Louis, MO 63110, USA; (C.B.); (G.B.-D.); (Y.F.); (A.A.); (B.E.)
| | - Yuanying Fang
- Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University in St. Louis, St. Louis, MO 63110, USA; (C.B.); (G.B.-D.); (Y.F.); (A.A.); (B.E.)
| | - Amer Avdagic
- Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University in St. Louis, St. Louis, MO 63110, USA; (C.B.); (G.B.-D.); (Y.F.); (A.A.); (B.E.)
| | - Bahaa Elgendy
- Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University in St. Louis, St. Louis, MO 63110, USA; (C.B.); (G.B.-D.); (Y.F.); (A.A.); (B.E.)
- Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Thomas P. Burris
- UF Genetics Institute, University of Florida, Gainesville, FL 32611, USA;
| | - Kristine Griffett
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| |
Collapse
|
|
23
|
Stifel U, Wolfschmitt EM, Vogt J, Wachter U, Vettorazzi S, Tews D, Hogg M, Zink F, Koll NM, Winning S, Mounier R, Chazaud B, Radermacher P, Fischer-Posovszky P, Caratti G, Tuckermann J. Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle. Mol Metab 2022; 57:101424. [PMID: 34954109 PMCID: PMC8783148 DOI: 10.1016/j.molmet.2021.101424] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVES Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs downregulate the expression of pro-inflammatory genes and upregulate the expression of anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tissue repair. It is currently unknown whether GCs control macrophage metabolism, and if so, to what extent metabolic regulation by GCs confers anti-inflammatory activity. METHODS Using transcriptomic and metabolomic profiling of macrophages, we identified GC-controlled pathways involved in metabolism, especially in mitochondrial function. RESULTS Metabolic analyses revealed that GCs repress glycolysis in inflammatory myeloid cells and promote tricarboxylic acid (TCA) cycle flux, promoting succinate metabolism and preventing intracellular accumulation of succinate. Inhibition of ATP synthase attenuated GC-induced transcriptional changes, likely through stalling of TCA cycle anaplerosis. We further identified a glycolytic regulatory transcription factor, HIF1α, as regulated by GCs, and as a key regulator of GC responsiveness during inflammatory challenge. CONCLUSIONS Our findings link metabolism to gene regulation by GCs in macrophages.
Collapse
Affiliation(s)
- Ulrich Stifel
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany
| | - Eva-Maria Wolfschmitt
- Institute for Anesthesiological Pathophysiology and Process Engineering, and Department of Anesthesiology, University Hospital, Ulm, Germany
| | - Josef Vogt
- Institute for Anesthesiological Pathophysiology and Process Engineering, and Department of Anesthesiology, University Hospital, Ulm, Germany
| | - Ulrich Wachter
- Institute for Anesthesiological Pathophysiology and Process Engineering, and Department of Anesthesiology, University Hospital, Ulm, Germany
| | - Sabine Vettorazzi
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany
| | - Daniel Tews
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatric and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Melanie Hogg
- Institute for Anesthesiological Pathophysiology and Process Engineering, and Department of Anesthesiology, University Hospital, Ulm, Germany
| | - Fabian Zink
- Institute for Anesthesiological Pathophysiology and Process Engineering, and Department of Anesthesiology, University Hospital, Ulm, Germany
| | - Nora Maria Koll
- Institut fürPhysiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122, Essen, Germany
| | - Sandra Winning
- Institut fürPhysiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122, Essen, Germany
| | - Rémi Mounier
- Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Université Lyon, Lyon, France
| | - Bénédicte Chazaud
- Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Université Lyon, Lyon, France
| | - Peter Radermacher
- Institute for Anesthesiological Pathophysiology and Process Engineering, and Department of Anesthesiology, University Hospital, Ulm, Germany
| | | | - Giorgio Caratti
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany.
| | - Jan Tuckermann
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Ulm, Germany.
| |
Collapse
|
|
24
|
Quattrocelli M, Wintzinger M, Miz K, Levine DC, Peek CB, Bass J, McNally EM. Muscle mitochondrial remodeling by intermittent glucocorticoid drugs requires an intact circadian clock and muscle PGC1α. SCIENCE ADVANCES 2022; 8:eabm1189. [PMID: 35179955 PMCID: PMC8856622 DOI: 10.1126/sciadv.abm1189] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 12/23/2021] [Indexed: 06/14/2023]
Abstract
Exogenous glucocorticoids interact with the circadian clock, but little attention is paid to the timing of intake. We recently found that intermittent once-weekly prednisone improved nutrient oxidation in dystrophic muscle. Here, we investigated whether dosage time affected prednisone effects on muscle bioenergetics. In mice treated with once-weekly prednisone, drug dosing in the light-phase promoted nicotinamide adenine dinucleotide (NAD+) levels and mitochondrial function in wild-type muscle, while this response was lost with dark-phase dosing. These effects depended on a normal circadian clock since they were disrupted in muscle from [Brain and muscle Arnt-like protein-1 (Bmal1)]-knockout mice. The light-phase prednisone pulse promoted BMAL1-dependent glucocorticoid receptor recruitment on noncanonical targets, including Nampt and Ppargc1a [peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α)]. In mice with muscle-restricted inducible PGC1α ablation, bioenergetic stimulation by light-phase prednisone required PGC1α. These results demonstrate that glucocorticoid "chronopharmacology" for muscle bioenergetics requires an intact clock and muscle PGC1α activity.
Collapse
Affiliation(s)
- Mattia Quattrocelli
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Michelle Wintzinger
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Karen Miz
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Daniel C. Levine
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Clara Bien Peek
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Joseph Bass
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Elizabeth M. McNally
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| |
Collapse
|
|
25
|
Huang S, Liu CH, Wang Z, Fu Z, Britton WR, Blomfield AK, Kamenecka TM, Dunaief JL, Solt LA, Chen J. REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2. Redox Biol 2022; 51:102261. [PMID: 35176707 PMCID: PMC8851379 DOI: 10.1016/j.redox.2022.102261] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 11/21/2022] Open
Abstract
Retinal pigment epithelium (RPE) dysfunction and atrophy occur in dry age-related macular degeneration (AMD), often leading to photoreceptor degeneration and vision loss. Accumulated oxidative stress during aging contributes to RPE dysfunction and degeneration. Here we show that the nuclear receptor REV-ERBα, a redox sensitive transcription factor, protects RPE from age-related degeneration and oxidative stress-induced damage. Genetic deficiency of REV-ERBα leads to accumulated oxidative stress, dysfunction and degeneration of RPE, and AMD-like ocular pathologies in aging mice. Loss of REV-ERBα exacerbates chemical-induced RPE damage, and pharmacological activation of REV-ERBα protects RPE from oxidative damage both in vivo and in vitro. REV-ERBα directly regulates transcription of nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase to counter oxidative damage. Moreover, aged mice with RPE specific knockout of REV-ERBα also exhibit accumulated oxidative stress and fundus and RPE pathologies. Together, our results suggest that REV-ERBα is a novel intrinsic protector of the RPE against age-dependent oxidative stress and a new molecular target for developing potential therapies to treat age-related retinal degeneration.
Collapse
|
|
26
|
Ray DW. Circadian Rhythm and Nuclear Receptors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:143-153. [PMID: 36107317 DOI: 10.1007/978-3-031-11836-4_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
All life of Earth has evolved mechanisms to track time. This permits anticipation of predictable changes in light/dark, and in most cases also directs fed/fasted cycles, and sleep/wake. The nuclear receptors enjoy a close relationship with the molecular machinery of the clock. Some play a core role within the circadian machinery, other respond to ligands which oscillate in concentration, and physical cross-talk between clock transcription factors, eg cryptochromes, and multiple nuclear receptors also enable coupling of nuclear receptor function to time of day. Essential processes including inflammation, and energy metabolism are strongly regulated by both the circadian machinery, and rhythmic behaviour, and also by multiple members of the nuclear receptor family. An emerging theme is reciprocal regulation of key processes by different members of the nuclear receptor family, for example NR1D1/2, and NR1F1, in regulation of the core circadian clock transcription factor BMAL1.
Collapse
|
|
27
|
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.
Collapse
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
| |
Collapse
|
|
28
|
Crislip GR, Johnston JG, Douma LG, Costello HM, Juffre A, Boyd K, Li W, Maugans CC, Gutierrez-Monreal M, Esser KA, Bryant AJ, Liu AC, Gumz ML. Circadian Rhythm Effects on the Molecular Regulation of Physiological Systems. Compr Physiol 2021; 12:2769-2798. [PMID: 34964116 PMCID: PMC11514412 DOI: 10.1002/cphy.c210011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Nearly every system within the body contains an intrinsic cellular circadian clock. The circadian clock contributes to the regulation of a variety of homeostatic processes in mammals through the regulation of gene expression. Circadian disruption of physiological systems is associated with pathophysiological disorders. Here, we review the current understanding of the molecular mechanisms contributing to the known circadian rhythms in physiological function. This article focuses on what is known in humans, along with discoveries made with cell and rodent models. In particular, the impact of circadian clock components in metabolic, cardiovascular, endocrine, musculoskeletal, immune, and central nervous systems are discussed. © 2021 American Physiological Society. Compr Physiol 11:1-30, 2021.
Collapse
Affiliation(s)
- G. Ryan Crislip
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | - Jermaine G. Johnston
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | | | - Hannah M. Costello
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | | | - Kyla Boyd
- Department of Biochemistry and Molecular Biology
| | - Wendy Li
- Department of Biochemistry and Molecular Biology
| | | | | | - Karyn A. Esser
- Department of Physiology and Functional Genomics
- Myology Institute
| | | | - Andrew C. Liu
- Department of Physiology and Functional Genomics
- Myology Institute
| | - Michelle L. Gumz
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
- Department of Biochemistry and Molecular Biology
- Department of Physiology and Functional Genomics
- Center for Integrative Cardiovascular and Metabolic Disease
| |
Collapse
|
|
29
|
Rong B, Wu Q, Saeed M, Sun C. Gut microbiota-a positive contributor in the process of intermittent fasting-mediated obesity control. ACTA ACUST UNITED AC 2021; 7:1283-1295. [PMID: 34786501 PMCID: PMC8567329 DOI: 10.1016/j.aninu.2021.09.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 09/12/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022]
Abstract
Historically, intermittent fasting (IF) has been considered as an effective strategy for controlling the weight of athletes before competition. Along with excellent insight into its application in various spaces by numerous studies, increasing IF-mediated positive effects have been reported, including anti-aging, neuroprotection, especially obesity control. Recently, the gut microbiota has been considered as an essential manipulator for host energy metabolism and its structure has been reported to be sensitive to dietary structure and habits, indicating that there is a potential and strong association between IF and gut microbiota. In this paper, we focus on the crosstalk between these symbionts and energy metabolism during IF which hold the promise to optimize host energy metabolism at various physical positions, including adipose tissue, liver and intestines, and further improve milieu internal homeostasis. Moreover, this paper also discusses the positive function of a potential recommendatory strain (Akkermansia muciniphila) based on the observational data for IF-mediated alternated pattern of gut microbiota and a hopefully regulatory pathway (circadian rhythm) for gut microbiota in IF-involved improvement on host energy metabolism. Finally, this review addresses the limitation and perspective originating from these studies, such as the association with tissue-specific bio-clock and single strain research, which may continuously reveal novel viewpoints and mechanisms to understand the energy metabolism and develop new strategies for treating obesity, diabetes, and metabolic disorders.
Collapse
Affiliation(s)
- Bohan Rong
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Qiong Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.,Department of Pathophysiology, Qinghai University Medical College, Xining, Qinghai, China
| | - Muhammad Saeed
- Faculty of Animal Production & Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63100, Pakistan
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| |
Collapse
|
|
30
|
The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6889533. [PMID: 34745420 PMCID: PMC8566046 DOI: 10.1155/2021/6889533] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022]
Abstract
The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.
Collapse
|
|
31
|
Briggs P, Hunter AL, Yang SH, Sharrocks AD, Iqbal M. PEGS: An efficient tool for gene set enrichment within defined sets of genomic intervals. F1000Res 2021; 10:570. [PMID: 34504687 PMCID: PMC8406447 DOI: 10.12688/f1000research.53926.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/25/2021] [Indexed: 11/28/2022] Open
Abstract
Many biological studies of transcriptional control mechanisms produce lists of genes and non-coding genomic intervals from corresponding gene expression and epigenomic assays. In higher organisms, such as eukaryotes, genes may be regulated by distal elements, with these elements lying 10s–100s of kilobases away from a gene transcription start site. To gain insight into these distal regulatory mechanisms, it is important to determine comparative enrichment of genes of interest in relation to genomic regions of interest, and to be able to do so at a range of distances. Existing bioinformatics tools can annotate genomic regions to nearest known genes, or look for transcription factor binding sites in relation to gene transcription start sites. Here, we present PEGS (
Peak set
Enrichment in
Gene
Sets). This tool efficiently provides an exploratory analysis by calculating enrichment of multiple gene sets, associated with multiple non-coding elements (peak sets), at multiple genomic distances, and within topologically associated domains. We apply PEGS to gene sets derived from gene expression studies, and genomic intervals from corresponding ChIP-seq and ATAC-seq experiments to derive biologically meaningful results. We also demonstrate an extended application to tissue-specific gene sets and publicly available GWAS data, to find enrichment of sleep trait associated SNPs in relation to tissue-specific gene expression profiles.
Collapse
Affiliation(s)
- Peter Briggs
- Bioinformatics Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
| | - A Louise Hunter
- Division of Diabetes, Endocrinology & Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
| | - Shen-Hsi Yang
- Division of Molecular & Cellular Function, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
| | - Andrew D Sharrocks
- Division of Molecular & Cellular Function, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
| | - Mudassar Iqbal
- Division of Informatics, Imaging & Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
| |
Collapse
|
|
32
|
Ishay Y, Kolben Y, Kessler A, Ilan Y. Role of circadian rhythm and autonomic nervous system in liver function: a hypothetical basis for improving the management of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2021; 321:G400-G412. [PMID: 34346773 DOI: 10.1152/ajpgi.00186.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.
Collapse
Affiliation(s)
- Yuval Ishay
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yotam Kolben
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Asa Kessler
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| |
Collapse
|
|
33
|
Giri A, Srinivasan A, Sundar IK. COVID-19: Sleep, Circadian Rhythms and Immunity - Repurposing Drugs and Chronotherapeutics for SARS-CoV-2. Front Neurosci 2021; 15:674204. [PMID: 34220430 PMCID: PMC8249936 DOI: 10.3389/fnins.2021.674204] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/05/2021] [Indexed: 01/08/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected nearly 28 million people in the United States and has caused more than five hundred thousand deaths as of February 21, 2021. As the novel coronavirus continues to take its toll in the United States and all across the globe, particularly among the elderly (>65 years), clinicians and translational researchers are taking a closer look at the nexus of sleep, circadian rhythms and immunity that may contribute toward a more severe coronavirus disease-19 (COVID-19). SARS-CoV-2-induced multi-organ failure affects both central and peripheral organs, causing increased mortality in the elderly. However, whether differences in sleep, circadian rhythms, and immunity between older and younger individuals contribute to the age-related differences in systemic dysregulation of target organs observed in SARS-CoV-2 infection remain largely unknown. Current literature demonstrates the emerging role of sleep, circadian rhythms, and immunity in the development of chronic pulmonary diseases and respiratory infections in human and mouse models. The exact mechanism underlying acute respiratory distress syndrome (ARDS) and other cardiopulmonary complications in elderly patients in combination with associated comorbidities remain unclear. Nevertheless, understanding the critical role of sleep, circadian clock dysfunction in target organs, and immune status of patients with SARS-CoV-2 may provide novel insights into possible therapies. Chronotherapy is an emerging concept that is gaining attention in sleep medicine. Accumulating evidence suggests that nearly half of all physiological functions follow a strict daily rhythm. However, healthcare professionals rarely take implementing timed-administration of drugs into consideration. In this review, we summarize recent findings directly relating to the contributing roles of sleep, circadian rhythms and immune response in modulating infectious disease processes, and integrate chronotherapy in the discussion of the potential drugs that can be repurposed to improve the treatment and management of COVID-19.
Collapse
Affiliation(s)
| | | | - Isaac Kirubakaran Sundar
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| |
Collapse
|
|
34
|
Zhuang X, Forde D, Tsukuda S, D'Arienzo V, Mailly L, Harris JM, Wing PAC, Borrmann H, Schilling M, Magri A, Rubio CO, Maidstone RJ, Iqbal M, Garzon M, Minisini R, Pirisi M, Butterworth S, Balfe P, Ray DW, Watashi K, Baumert TF, McKeating JA. Circadian control of hepatitis B virus replication. Nat Commun 2021; 12:1658. [PMID: 33712578 PMCID: PMC7955118 DOI: 10.1038/s41467-021-21821-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
Collapse
Affiliation(s)
- Xiaodong Zhuang
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Donall Forde
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Senko Tsukuda
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- RIKEN Cluster for Pioneering Research, Wako, Japan
| | | | - Laurent Mailly
- University of Strasbourg and Inserm, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
| | - James M Harris
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Peter A C Wing
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Helene Borrmann
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Mirjam Schilling
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Andrea Magri
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | - Robert J Maidstone
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Mudassar Iqbal
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Miguel Garzon
- Division of Pharmacy and Optometry, School of Health Sciences and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Sam Butterworth
- Division of Pharmacy and Optometry, School of Health Sciences and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
| | - Peter Balfe
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - David W Ray
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- RIKEN Cluster for Pioneering Research, Wako, Japan
- Department of Applied Biological Sciences, Tokyo University of Science Graduate School of Science and Technology, Japan and Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Thomas F Baumert
- University of Strasbourg and Inserm, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Pôle Hépato-Digestif, Institut Hopitalo-Universitaire (IHU), Hopitaux Universitaire de Strasbourg, Strasbourg and Institut Universitaire de France, Paris, France
| | - Jane A McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| |
Collapse
|
|
35
|
Bartman CM, Matveyenko A, Pabelick C, Prakash YS. Cellular clocks in hyperoxia effects on [Ca 2+] i regulation in developing human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2021; 320:L451-L466. [PMID: 33404366 PMCID: PMC8294620 DOI: 10.1152/ajplung.00406.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/24/2020] [Accepted: 12/31/2020] [Indexed: 01/06/2023] Open
Abstract
Supplemental O2 (hyperoxia) is necessary for preterm infant survival but is associated with development of bronchial airway hyperreactivity and childhood asthma. Understanding early mechanisms that link hyperoxia to altered airway structure and function are key to developing advanced therapies. We previously showed that even moderate hyperoxia (50% O2) enhances intracellular calcium ([Ca2+]i) and proliferation of human fetal airway smooth muscle (fASM), thereby facilitating bronchoconstriction and remodeling. Here, we introduce cellular clock biology as a novel mechanism linking early oxygen exposure to airway biology. Peripheral, intracellular clocks are a network of transcription-translation feedback loops that produce circadian oscillations with downstream targets highly relevant to airway function and asthma. Premature infants suffer circadian disruption whereas entrainment strategies improve outcomes, highlighting the need to understand relationships between clocks and developing airways. We hypothesized that hyperoxia impacts clock function in fASM and that the clock can be leveraged to attenuate deleterious effects of O2 on the developing airway. We report that human fASM express core clock machinery (PER1, PER2, CRY1, ARNTL/BMAL1, CLOCK) that is responsive to dexamethasone (Dex) and altered by O2. Disruption of the clock via siRNA-mediated PER1 or ARNTL knockdown alters store-operated calcium entry (SOCE) and [Ca2+]i response to histamine in hyperoxia. Effects of O2 on [Ca2+]i are rescued by driving expression of clock proteins, via effects on the Ca2+ channels IP3R and Orai1. These data reveal a functional fASM clock that modulates [Ca2+]i regulation, particularly in hyperoxia. Harnessing clock biology may be a novel therapeutic consideration for neonatal airway diseases following prematurity.
Collapse
Affiliation(s)
- Colleen M Bartman
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Aleksey Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Christina Pabelick
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Y S Prakash
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
36
|
Abstract
The circadian clock controls several aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. Our circadian rhythms are driven by an endogenous central clock in the brain that synchronizes with clocks in peripheral tissues, thereby regulating our immune system and the severity of infections. These rhythms affect the pharmacokinetics and efficacy of therapeutic agents and vaccines. The core circadian regulatory circuits and clock-regulated host pathways provide fertile ground to identify novel antiviral therapies. An increased understanding of the role circadian systems play in regulating virus infection and the host response to the virus will inform our clinical management of these diseases. This review provides an overview of the experimental and clinical evidence reporting on the interplay between the circadian clock and viral infections, highlighting the importance of virus-clock research.
Collapse
Affiliation(s)
- Helene Borrmann
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | | | - Xiaodong Zhuang
- Xiaodong Zhuang, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK; e-mail:
| |
Collapse
|
|
37
|
Qiu MJ, Zhang L, Fang XF, Li QT, Zhu LS, Zhang B, Yang SL, Xiong ZF. Research on the circadian clock gene HNF4a in different malignant tumors. Int J Med Sci 2021; 18:1339-1347. [PMID: 33628089 PMCID: PMC7893568 DOI: 10.7150/ijms.49997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 01/04/2021] [Indexed: 11/28/2022] Open
Abstract
Background: The circadian rhythm is produced by multiple feedback loops formed by the core clock genes after transcription and translation, thus regulating various metabolic and physiological functions of the human body. We have shown previously that the abnormal expression of 14 clock genes is related closely to the occurrence and development of different malignant tumors, and these genes may play an anti-cancer or pro-cancer role in different tumors. HNF4a has many typical properties of clock proteins involved in the clock gene negative feedback loop regulation process. We need to explore the function of HNF4a as a circadian clock gene in malignant tumors further. Methods: We used The Cancer Genome Atlas (TCGA) database to download the clinicopathological information of twenty malignant tumors and the corresponding RNA-seq data. The HNF4a RNA-seq data standardized by R language and clinical information were integrated to reveal the relationship between HNF4a and prognosis of patients. Results: Analysis of TCGA data showed that the prognosis of HNF4a was significantly different in BLCA, KIRC, LUSC, and READ. High HNF4a expression is correlated with good prognosis in BLCA, KIRC, and READ but poor prognosis in LUSC. However, HNF4a was associated with the stages, T stages, and lymph node status only in BLCA. Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA. The low expression of HNF4a could be a reference index for the metastasis, recurrence, and prognosis of BLCA.
Collapse
Affiliation(s)
- Meng-Jun Qiu
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Li Zhang
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Xie-Fan Fang
- Charles River Laboratories, Inc., 6995 Longley Lane, Reno NV 89511
| | - Qiu-Ting Li
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Li-Sheng Zhu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bin Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Sheng-Li Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhi-Fan Xiong
- Division of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| |
Collapse
|
|
38
|
Xiao Y, Kim M, Lazar MA. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab 2020; 50:101119. [PMID: 33220489 PMCID: PMC8324695 DOI: 10.1016/j.molmet.2020.101119] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As a result of a sedentary lifestyle and excess food consumption in modern society, non-alcoholic fatty liver disease (NAFLD) characterized by fat accumulation in the liver is becoming a major disease burden. Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by inflammation and fibrosis that can lead to hepatocellular carcinoma and liver failure. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that closely control multiple aspects of metabolism. Their transcriptional activity is modulated by various ligands, including hormones and lipids. NRs serve as potential pharmacological targets for NAFLD/NASH and other metabolic diseases. SCOPE OF REVIEW In this review, we provide a comprehensive overview of NRs that have been studied in the context of NAFLD/NASH with a focus on their transcriptional regulation, function in preclinical models, and studies of their clinical utility. MAJOR CONCLUSIONS The transcriptional regulation of NRs is context-dependent. During the dynamic progression of NAFLD/NASH, NRs play diverse roles in multiple organs and different cell types in the liver, which highlights the necessity of targeting NRs in a stage-specific and cell-type-specific manner to enhance the efficacy and safety of treatment methods.
Collapse
Affiliation(s)
- Yang Xiao
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mindy Kim
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
39
|
Kanki M, Young MJ. Corticosteroids and circadian rhythms in the cardiovascular system. Curr Opin Pharmacol 2020; 57:21-27. [PMID: 33207294 DOI: 10.1016/j.coph.2020.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/19/2022]
Abstract
The mineralocorticoid receptor (MR) plays a central role in cardiac physiological function and disease and is thus an attractive therapeutic target for patients with heart failure. However, the incidence of significant side effects from mineralocorticoid receptor antagonist (MRA) treatment has led to investigation of new mechanisms that may enhance MR targeted therapies. Recent studies have identified the circadian clock as a novel, reciprocal interacting partner of the MR in the heart. While the closely related glucocorticoid receptor (GR) and its ligand, cortisol (corticosterone in rodents), are established regulators of the circadian clock, new data suggest that the MR can also regulate circadian clock gene expression and timing. This review will discuss the role of the MR and its ligands in the regulation of the circadian clock in the heart and the implications of dysregulation of these systems for cardiac disease progression, and for MR activation.
Collapse
Affiliation(s)
- Monica Kanki
- Cardiovascular Endocrinology Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia; Cardiovascular Endocrinology Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular & Translational Science, Monash University, Clayton, VIC, Australia
| | - Morag J Young
- Cardiovascular Endocrinology Laboratory, Baker Heart & Diabetes Institute, Melbourne, VIC, Australia; Cardiovascular Endocrinology Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular & Translational Science, Monash University, Clayton, VIC, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia.
| |
Collapse
|
|
40
|
Præstholm SM, Correia CM, Grøntved L. Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism. Front Endocrinol (Lausanne) 2020; 11:572981. [PMID: 33133019 PMCID: PMC7578419 DOI: 10.3389/fendo.2020.572981] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/03/2020] [Indexed: 12/14/2022] Open
Abstract
Glucocorticoids (GCs) and the glucocorticoid receptor (GR) are important regulators of development, inflammation, stress response and metabolism, demonstrated in various diseases including Addison's disease, Cushing's syndrome and by the many side effects of prolonged clinical administration of GCs. These conditions include severe metabolic challenges in key metabolic organs like the liver. In the liver, GR is known to regulate the transcription of key enzymes in glucose and lipid metabolism and contribute to the regulation of circadian-expressed genes. Insights to the modes of GR regulation and the underlying functional mechanisms are key for understanding diseases and for the development of improved clinical uses of GCs. The activity and function of GR is regulated at numerous levels including ligand availability, interaction with heat shock protein (HSP) complexes, expression of GR isoforms and posttranslational modifications. Moreover, recent genomics studies show functional interaction with multiple transcription factors (TF) and coregulators in complex transcriptional networks controlling cell type-specific gene expression by GCs. In this review we describe the different regulatory steps important for GR activity and discuss how different TF interaction partners of GR selectively control hepatic gene transcription and metabolism.
Collapse
Affiliation(s)
| | | | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| |
Collapse
|
|
41
|
Li Y, Ma J, Yao K, Su W, Tan B, Wu X, Huang X, Li T, Yin Y, Tosini G, Yin J. Circadian rhythms and obesity: Timekeeping governs lipid metabolism. J Pineal Res 2020; 69:e12682. [PMID: 32656907 DOI: 10.1111/jpi.12682] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/02/2020] [Accepted: 07/07/2020] [Indexed: 12/29/2022]
Abstract
Almost all living organisms have evolved autoregulatory transcriptional-translational feedback loops that produce oscillations with a period of approximately 24-h. These endogenous time keeping mechanisms are called circadian clocks. The main function of these circadian clocks is to drive overt circadian rhythms in the physiology of the organisms to ensure that main physiological functions are in synchrony with the external environment. Disruption of circadian rhythms caused by genetic or environmental factors has long-term consequences for metabolic health. Of relevance, host circadian rhythmicity and lipid metabolism are increasingly recognized to cross-regulate and the circadian clock-lipid metabolism interplay may involve in the development of obesity. Multiple systemic and molecular mechanisms, such as hormones (ie, melatonin, leptin, and glucocorticoid), the gut microbiome, and energy metabolism, link the circadian clock and lipid metabolism, and predictably, the deregulation of circadian clock-lipid metabolism interplay can increase the risk of obesity, which in turn may exacerbate circadian disorganization. Feeding time and dietary nutrients are two of key environmental Zeitgebers affecting the circadian rhythm-lipid metabolism interplay, and the influencing mechanisms in obesity development are highlighted in this review. Together, the characterization of the clock machinery in lipid metabolism aimed at producing a healthy circadian lifestyle may improve obesity care.
Collapse
Affiliation(s)
- Yuying Li
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jie Ma
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Kang Yao
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Wenxuan Su
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Bie Tan
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Xin Wu
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Xingguo Huang
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Tiejun Li
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Yulong Yin
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | - Jie Yin
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| |
Collapse
|
|
42
|
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.
Collapse
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
| |
Collapse
|
|
43
|
Borrmann H, Davies R, Dickinson M, Pedroza-Pacheco I, Schilling M, Vaughan-Jackson A, Magri A, James W, Balfe P, Borrow P, McKeating JA, Zhuang X. Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication. Sci Rep 2020; 10:13271. [PMID: 32764708 PMCID: PMC7413328 DOI: 10.1038/s41598-020-70170-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 07/07/2020] [Indexed: 12/18/2022] Open
Abstract
Human immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks a curative therapy or vaccine. Despite the reduction in AIDS-related deaths achieved by current antiretroviral therapies, drawbacks including drug resistance and the failure to eradicate infection highlight the need to identify new pathways to target the infection. Circadian rhythms are endogenous 24-h oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components in regulating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, BMAL1 and CLOCK activate rhythmic transcription of genes including the nuclear receptor REV-ERBα, which represses BMAL1 and plays an essential role in sustaining a functional clock. We investigated whether REV-ERB activity regulates HIV-1 replication and found REV-ERB agonists inhibited HIV-1 promoter activity in cell lines, primary human CD4 T cells and macrophages, whilst antagonism or genetic disruption of REV-ERB increased promoter activity. The REV-ERB agonist SR9009 inhibited promoter activity of diverse HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic agonists to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock components in regulating HIV-1 replication.
Collapse
Affiliation(s)
- Helene Borrmann
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Rhianna Davies
- Institute of Immunity and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, UK
| | - Matthew Dickinson
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | | | - Mirjam Schilling
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | | | - Andrea Magri
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - William James
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
| | - Peter Balfe
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Persephone Borrow
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Jane A McKeating
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Xiaodong Zhuang
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
| |
Collapse
|
|
44
|
Wang S, Li F, Lin Y, Wu B. Targeting REV-ERBα for therapeutic purposes: promises and challenges. Theranostics 2020; 10:4168-4182. [PMID: 32226546 PMCID: PMC7086371 DOI: 10.7150/thno.43834] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 02/08/2020] [Indexed: 12/12/2022] Open
Abstract
REV-ERBα (NR1D1) is a circadian clock component that functions as a transcriptional repressor. Due to its role in direct modulation of metabolic genes, REV-ERBα is regarded as an integrator of cell metabolism with circadian clock. Accordingly, REV-ERBα is first proposed as a drug target for treating sleep disorders and metabolic syndromes (e.g., dyslipidaemia, hyperglycaemia and obesity). Recent years of studies uncover a rather broad role of REV-ERBα in pathological conditions including local inflammatory diseases, heart failure and cancers. Moreover, REV-ERBα is involved in regulation of circadian drug metabolism that has implications in chronopharmacology. In the meantime, recent years have witnessed discovery of an array of new REV-ERBα ligands most of which have pharmacological activities in vivo. In this article, we review the regulatory role of REV-ERBα in various types of diseases and discuss the underlying mechanisms. We also describe the newly discovered ligands and the old ones together with their targeting potential. Despite well-established pharmacological effects of REV-ERBα ligands in animals (preclinical studies), no progress has been made regarding their translation to clinical trials. This implies certain challenges associated with drug development of REV-ERBα ligands. In particular, we discuss the potential challenges related to drug safety (or adverse effects) and bioavailability. For new drug development, it is advocated that REV-ERBα should be targeted to treat local diseases and a targeting drug should be locally distributed, avoiding the adverse effects on other tissues.
Collapse
Affiliation(s)
- Shuai Wang
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
- Integrated Chinese and Western Medicine Postdoctoral research station, Jinan University, Guangzhou, 510632, China
| | - Feng Li
- Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, 510632, China
| | - Yanke Lin
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Baojian Wu
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China
| |
Collapse
|
|
45
|
Ray S, Valekunja UK, Stangherlin A, Howell SA, Snijders AP, Damodaran G, Reddy AB. Circadian rhythms in the absence of the clock gene Bmal1. Science 2020; 367:800-806. [PMID: 32054765 DOI: 10.1126/science.aaw7365] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 07/18/2019] [Accepted: 01/14/2020] [Indexed: 12/14/2022]
Abstract
Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether Bmal1 function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.
Collapse
Affiliation(s)
- Sandipan Ray
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Utham K Valekunja
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alessandra Stangherlin
- Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | | | | | | | - Akhilesh B Reddy
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Chronobiology and Sleep institute (CSI), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| |
Collapse
|
|
46
|
Abstract
Circadian rhythms are daily cycles in biological function that are ubiquitous in nature. Understood as a means for organisms to anticipate daily environmental changes, circadian rhythms are also important for orchestrating complex biological processes such as immunity. Nowhere is this more evident than in the respiratory system, where circadian rhythms in inflammatory lung disease have been appreciated since ancient times. In this focused review we examine how emerging research on circadian rhythms is being applied to the study of fundamental lung biology and respiratory disease. We begin with a general introduction to circadian rhythms and the molecular circadian clock that underpins them. We then focus on emerging data tying circadian clock function to immunologic activities within the respiratory system. We conclude by considering outstanding questions about biological timing in the lung and how a better command of chronobiology could inform our understanding of complex lung diseases.
Collapse
Affiliation(s)
- Charles Nosal
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Anna Ehlers
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Jeffrey A Haspel
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| |
Collapse
|
|
47
|
Hardy RS, Raza K, Cooper MS. Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases. Nat Rev Rheumatol 2020; 16:133-144. [PMID: 32034322 DOI: 10.1038/s41584-020-0371-y] [Citation(s) in RCA: 154] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2020] [Indexed: 12/11/2022]
Abstract
Therapeutic glucocorticoids have been widely used in rheumatic diseases since they became available over 60 years ago. Despite the advent of more specific biologic therapies, a notable proportion of individuals with chronic rheumatic diseases continue to be treated with these drugs. Glucocorticoids are powerful, broad-spectrum anti-inflammatory agents, but their use is complicated by an equally broad range of adverse effects. The specific cellular mechanisms by which glucocorticoids have their therapeutic action have been difficult to identify, and attempts to develop more selective drugs on the basis of the action of glucocorticoids have proven difficult. The actions of glucocorticoids seem to be highly cell-type and context dependent. Despite emerging data on the effect of tissue-specific manipulation of glucocorticoid receptors in mouse models of inflammation, the cell types and intracellular targets of glucocorticoids in rheumatic diseases have not been fully identified. Although showing some signs of decline, the use of systemic glucocorticoids in rheumatology is likely to continue to be widespread, and careful consideration is required by rheumatologists to balance the beneficial effects and deleterious effects of these agents.
Collapse
Affiliation(s)
- Rowan S Hardy
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Karim Raza
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Mark S Cooper
- ANZAC Research Institute, University of Sydney, Sydney, Australia.
| |
Collapse
|
|
48
|
Almeida S, Chaves M, Delaunay F. Control of synchronization ratios in clock/cell cycle coupling by growth factors and glucocorticoids. ROYAL SOCIETY OPEN SCIENCE 2020; 7:192054. [PMID: 32257354 PMCID: PMC7062057 DOI: 10.1098/rsos.192054] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/17/2020] [Indexed: 05/06/2023]
Abstract
The cell cycle and the circadian clock are essential cyclic cellular processes often synchronous in healthy cells. In this work, we use previously developed mathematical models of the mammalian cell cycle and circadian cellular clock in order to investigate their dynamical interactions. Firstly, we study unidirectional cell cycle → clock coupling by proposing a mechanism of mitosis promoting factor (MPF)-controlled REV-ERBα degradation. Secondly, we analyse a bidirectional coupling configuration, where we add the CLOCK : BMAL1-mediated MPF repression via the WEE1 kinase to the first system. Our simulations reproduce ratios of clock to cell cycle period in agreement with experimental observations and give predictions of the system's synchronization state response to a variety of control parameters. Specifically, growth factors accelerate the coupled oscillators and dexamethasone (Dex) drives the system from a 1 : 1 to a 3 : 2 synchronization state. Furthermore, simulations of a Dex pulse reveal that certain time regions of pulse application drive the system from 1 : 1 to 3 : 2 synchronization while others have no effect, revealing the existence of a responsive and an irresponsive system's phase, a result we contextualize with observations on the segregation of Dex-treated cells into two populations.
Collapse
Affiliation(s)
- S. Almeida
- Université Côte d’Azur, iBV, Inria, Biocore team, Sophia Antipolis, France
| | - M. Chaves
- Université Côte d’Azur, Inria, INRA, CNRS, Sorbonne Université, Biocore team, Sophia Antipolis, France
| | - F. Delaunay
- Université Côte d’Azur, CNRS, INSERM, iBV, Nice, France
| |
Collapse
|
|
49
|
Downton P, Early JO, Gibbs JE. Circadian rhythms in adaptive immunity. Immunology 2020; 161:268-277. [PMID: 31837013 DOI: 10.1111/imm.13167] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 10/31/2019] [Accepted: 12/05/2019] [Indexed: 12/11/2022] Open
Abstract
The circadian clock provides organisms with the ability to track time of day, allowing them to predict and respond to cyclical changes in the external environment. In mammals this clock consists of multiple auto-regulatory feedback loops generated by a network of circadian clock proteins. This network provides the fundamental basis for rhythms in behaviour and physiology. This clockwork machinery exists in most cells, including those of the immune system. In recent years evidence has emerged highlighting the important role of molecular clocks in dictating the response of immune pathways. While initial work highlighted the effect of the clock in the 'first line of defence', the innate immune system, it has become increasingly apparent that it also plays a role in the more tailored, later-stage adaptive immune response. This review provides an overview of the role of the circadian cycle in the adaptive immune response. We interrogate the depth of knowledge on cell intrinsic clocks within adaptive immune cells and how these cells may be temporally directed by extrinsic rhythmic signals. We discuss the role of the circadian clock in diseases associated with adaptive immunity such as multiple sclerosis, asthma and parasitic infection. We also discuss the current knowledge on timing of vaccination, and the implications this may have on how we can harness and modulate temporal gating of the adaptive immune response in a clinical setting.
Collapse
Affiliation(s)
- Polly Downton
- Centre for Biogical Timing, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - James O Early
- Centre for Biogical Timing, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Julie E Gibbs
- Centre for Biogical Timing, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| |
Collapse
|
|
50
|
Haspel JA, Anafi R, Brown MK, Cermakian N, Depner C, Desplats P, Gelman AE, Haack M, Jelic S, Kim BS, Laposky AD, Lee YC, Mongodin E, Prather AA, Prendergast BJ, Reardon C, Shaw AC, Sengupta S, Szentirmai É, Thakkar M, Walker WE, Solt LA. Perfect timing: circadian rhythms, sleep, and immunity - an NIH workshop summary. JCI Insight 2020; 5:131487. [PMID: 31941836 PMCID: PMC7030790 DOI: 10.1172/jci.insight.131487] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.
Collapse
Affiliation(s)
- Jeffrey A. Haspel
- Division of Pulmonary, Critical Care and Sleep Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Ron Anafi
- Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Marishka K. Brown
- National Center on Sleep Disorders Research, Division of Lung Diseases, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Nicolas Cermakian
- Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Christopher Depner
- Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA
| | - Paula Desplats
- Department of Neurosciences and
- Department of Pathology, UCSD, La Jolla, California, USA
| | - Andrew E. Gelman
- Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Monika Haack
- Human Sleep and Inflammatory Systems Laboratory, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Sanja Jelic
- Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University School of Medicine, New York, New York, USA
| | - Brian S. Kim
- Center for the Study of Itch
- Department of Medicine
- Department of Anesthesiology
- Department of Pathology, and
- Department of Immunology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Aaron D. Laposky
- National Center on Sleep Disorders Research, Division of Lung Diseases, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Yvonne C. Lee
- Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Emmanuel Mongodin
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Aric A. Prather
- Department of Psychiatry, UCSF, San Francisco, California, USA
| | - Brian J. Prendergast
- Department of Psychology and Committee on Neurobiology, University of Chicago, Chicago, Illinois, USA
| | - Colin Reardon
- Department, of Anatomy, Physiology, and Cell Biology, UCD School of Veterinary Medicine, Davis, California, USA
| | - Albert C. Shaw
- Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Shaon Sengupta
- Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Éva Szentirmai
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington, USA
| | - Mahesh Thakkar
- Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, USA
- Department of Neurology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Wendy E. Walker
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Health Sciences Center, Texas Tech University, El Paso, Texas, USA
| | - Laura A. Solt
- Department of Immunology and Microbiology, Scripps Research Institute, Jupiter, Florida, USA
| |
Collapse
|