Biology of the orphan receptor Rev-erb alpha

Summary

Principal Investigator: Mitchell A Lazar
Abstract: DESCRIPTION (provided by applicant): Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the US. Recent discoveries implicate the nuclear receptor Rev-erb1 as a transcriptional link between the circadian clock and metabolism. The present proposal combines tissue-specific, genome-wide analysis of TF binding and epigenomic modifications, novel mouse genetic models, and sophisticated metabolic phenotyping to understand the physiological role of Rev-erb1 and Rev-erb2 in the coordination of circadian rhythms and metabolism. Specific Aim 1 is to determine the role of Rev-erb1 in the regulation of hepatic circadian rhythm and metabolism. The liver is a critical metabolic organ, and our preliminary data demonstrate fatty liver in mice lacking Rev-erb1. Genome-wide analysis of Rev-erb1 binding sites identifies lipid metabolic genes to which HDAC3 is recruited in a circadian manner. We hypothesize that this is a critical mechanism of circadian epigenomic control of hepatic lipid metabolism, and will test this by a combination of genome-wide approaches in informative and carefully phenotyped mouse genetic models. Specific Aim 2 is to determine the role of Rev-erb1 in adipose circadian rhythm and metabolism. Preliminary data show that mice lacking Rev-erb1 have increased white adipose tissue, and genome-wide analysis reveals binding of Rev-erb1 to a distinct set of metabolic genes. We will test the hypothesis that Rev-erb1 epigenomically controls fat- specific functions together with cooperating transcription factors. Specific Aim 3 is to determine the role of Rev- erb1 stabilization in circadian rhythm and metabolism, utilizing a novel mouse model in which Rev-erb1 is insensitive to the lithium-stimulated degradation pathway. Specific Aim 4 is to determine the role of Rev-erb2 in the regulation of circadian rhythm and metabolism. Knockdown and knockout models will test the hypothesis that Rev-erb2 has circadian and metabolic functions that are both unique and partly redundant with Rev-erb1. These integrative studies have important implications for understanding the links between circadian rhythm and metabolism that underlie the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.
Funding Period: 1992-09-30 - 2016-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock
    Lei Yin
    Division of Endocrinology, Diabetes, and Metabolism, and University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA
    Science 311:1002-5. 2006
  2. pmc A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism
    Dan Feng
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Science 331:1315-9. 2011
  3. pmc Circadian epigenomic remodeling and hepatic lipogenesis: lessons from HDAC3
    Z Sun
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Cold Spring Harb Symp Quant Biol 76:49-55. 2011
  4. pmc Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function
    Anne Bugge
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 26:657-67. 2012
  5. pmc Clocks, metabolism, and the epigenome
    Dan Feng
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Mol Cell 47:158-67. 2012
  6. pmc Dissociating fatty liver and diabetes
    Zheng Sun
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Trends Endocrinol Metab 24:4-12. 2013
  7. pmc Obesity in mice with adipocyte-specific deletion of clock component Arntl
    Georgios K Paschos
    Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Nat Med 18:1768-77. 2012
  8. pmc Cell-specific integration of nuclear receptor function at the genome
    Logan J Everett
    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Wiley Interdiscip Rev Syst Biol Med 5:615-29. 2013
  9. pmc The orphan nuclear receptors at their 25-year reunion
    Shannon E Mullican
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Mol Endocrinol 51:T115-40. 2013
  10. pmc The nuclear receptor Rev-erbα controls circadian thermogenic plasticity
    Zachary Gerhart-Hines
    1 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA 2 The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nature 503:410-3. 2013

Research Grants

  1. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
  2. Regulation of cholesterol catabolism by bile acids
    Jongsook Kim Kemper; Fiscal Year: 2013
  3. Role of Ror proteins in the mammalian circadian clock
    Steve A Kay; Fiscal Year: 2013
  4. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
  5. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
  6. Effects of sleep deprivation and high fat diet on human CYP7A1 circadian rhythm
    JESSICA MARIE FERRELL; Fiscal Year: 2013
  7. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  8. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
  9. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013

Detail Information

Publications22

  1. ncbi Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock
    Lei Yin
    Division of Endocrinology, Diabetes, and Metabolism, and University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA
    Science 311:1002-5. 2006
    ..Control of Rev-erbalpha protein stability is thus a critical component of the peripheral clock and a biological target of lithium therapy...
  2. pmc A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism
    Dan Feng
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Science 331:1315-9. 2011
    ..Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis...
  3. pmc Circadian epigenomic remodeling and hepatic lipogenesis: lessons from HDAC3
    Z Sun
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Cold Spring Harb Symp Quant Biol 76:49-55. 2011
    ..Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver...
  4. pmc Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function
    Anne Bugge
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 26:657-67. 2012
    ....
  5. pmc Clocks, metabolism, and the epigenome
    Dan Feng
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Mol Cell 47:158-67. 2012
    ..Here we review the recent advances in understanding the crosstalk between the circadian clock and energy metabolism through epigenomic programming and transcriptional regulation...
  6. pmc Dissociating fatty liver and diabetes
    Zheng Sun
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Trends Endocrinol Metab 24:4-12. 2013
    ....
  7. pmc Obesity in mice with adipocyte-specific deletion of clock component Arntl
    Georgios K Paschos
    Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Nat Med 18:1768-77. 2012
    ..Thus, this study reveals a role for the adipocyte clock in the temporal organization of energy regulation, highlights timing as a modulator of the adipocyte-hypothalamic axis and shows the impact of timing of food intake on body weight...
  8. pmc Cell-specific integration of nuclear receptor function at the genome
    Logan J Everett
    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Wiley Interdiscip Rev Syst Biol Med 5:615-29. 2013
    ..Emerging genomic technologies such as ChIP-seq and GRO-seq provide insights on a larger scale leading to deeper understanding of the complexities of transcriptional regulation by NRs...
  9. pmc The orphan nuclear receptors at their 25-year reunion
    Shannon E Mullican
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Mol Endocrinol 51:T115-40. 2013
    ..Here we provide a compendium of these so-called orphan receptors and focus on what has been learned about their modes of action, physiological functions, and therapeutic promise. ..
  10. pmc The nuclear receptor Rev-erbα controls circadian thermogenic plasticity
    Zachary Gerhart-Hines
    1 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA 2 The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nature 503:410-3. 2013
    ..Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands. ..
  11. pmc Endogenous ligands for nuclear receptors: digging deeper
    Michael Schupp
    Department of Endocrinology, Diabetes, and Nutrition and Center for Cardiovascular Research, Institute of Pharmacology, Charite University Medicine Berlin, 10115 Berlin, Germany
    J Biol Chem 285:40409-15. 2010
    ..This knowledge about the nature and physiology of these ligands may create new opportunities for therapeutic drug development...
  12. pmc Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding
    Xin Tong
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
    J Biol Chem 285:36401-9. 2010
    ..Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding...
  13. ncbi The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1
    Jing Wang
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA
    J Biol Chem 281:33842-8. 2006
    ..Thus, our results suggest that Rev-erb alpha is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction...
  14. ncbi The corepressor silencing mediator for retinoid and thyroid hormone receptor facilitates cellular recovery from DNA double-strand breaks
    Jiujiu Yu
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6149, USA
    Cancer Res 66:9316-22. 2006
    ..Thus, the corepressor SMRT plays a novel and critical role in the cellular response to DSBs...
  15. ncbi Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways
    Lei Yin
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Science 318:1786-9. 2007
    ..Thus, Rev-erbalpha serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism...
  16. pmc Bifunctional role of Rev-erbalpha in adipocyte differentiation
    Jing Wang
    University of Pennsylvania School of Medicine, 700 CRB, 415 Curie Blvd, Philadelphia, PA 19104 6149, USA
    Mol Cell Biol 28:2213-20. 2008
    ..Thus, opposite to what might be predicted from Rev-erbalpha gene expression, Rev-erbalpha protein levels must rise and then fall for adipocyte differentiation to occur...
  17. pmc Selective partial agonism of liver X receptor alpha is related to differential corepressor recruitment
    Caroline A Phelan
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Mol Endocrinol 22:2241-9. 2008
    ..Thus, differential recruitment of NCoR is a major determinant of partial agonism and selective LXR modulation of target genes...
  18. pmc Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha
    Nan Wu
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 23:2201-9. 2009
    ..Thus, Rev-erbalpha modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism...
  19. pmc Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism
    Lei Yin
    University of Michigan School of Medicine, Ann Arbor, Michigan, USA
    Nucl Recept Signal 8:e001. 2010
    ..Rev-erbalpha also regulates the metabolic gene pathway, thus serving as a heme sensor for coordination of circadian and metabolic pathways...
  20. pmc E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha
    Lei Yin
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 107:11614-9. 2010
    ..Thus, Arf-bp1 and Pam are novel regulators of circadian gene expression that target Rev-erb alpha for degradation...
  21. pmc Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction
    Caroline A Phelan
    Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Genetics, The Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Nat Struct Mol Biol 17:808-14. 2010
    ..The previously uncharacterized secondary structure induced by ID1 peptide binding advances our understanding of nuclear receptor-co-repressor interactions...
  22. pmc Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbα
    Jennifer Jager
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism J J, B F, Z G H, M A L, Department of Neurosciences W T O, J M, and Division of Hematology Oncology, Department of Medicine P S K, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104 and Children s Hospital of Philadelphia Research Institute E N K, M B R, Departments of Pediatrics and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    Mol Endocrinol 28:490-8. 2014
    ..These findings reveal a novel, nonredundant function for Rev-erbα that links a core component of the circadian gene-regulatory network to the control of dopaminergic and hippocampus-dependent behaviors. ..

Research Grants30

  1. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
    ....
  2. Regulation of cholesterol catabolism by bile acids
    Jongsook Kim Kemper; Fiscal Year: 2013
    ..These studies will elucidate how SHP epigenetically controls BA-regulated hepatic functions, and identify novel potential diagnostic and/or therapeutic targets for metabolic diseases. ..
  3. Role of Ror proteins in the mammalian circadian clock
    Steve A Kay; Fiscal Year: 2013
    ....
  4. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  5. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  6. Effects of sleep deprivation and high fat diet on human CYP7A1 circadian rhythm
    JESSICA MARIE FERRELL; Fiscal Year: 2013
    ..The proposed studies aim to understand the contribution of deregulated circadian liver metabolism in the progression of diabetes and obesity. ..
  7. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  8. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  9. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  11. HORMONAL REGULATION OF MAMMALIAN GENE EXPRESSION
    Ronald M Evans; Fiscal Year: 2013
    ....
  12. Novel targets that are deregulated by loss of PTEN
    Deborah Johnson; Fiscal Year: 2013
    ..If successful, these studies will identify a novel role for Maf1 as a central coordinator of metabolic signals and will thus provide a new molecular mechanism for the long-known association between obesity and cancer. ..
  13. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  14. Role of stearoyl CoA desaturase-1 in TLR5 KO mice colitis and metabolic syndrome
    Matam Vijay Kumar; Fiscal Year: 2013
    ..Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify whether SCD-1 can be targeted to prevent colitis and metabolic diseases ! ..
  15. NUCLEAR HORMONE RECEPTORS IN ADIPOCYTE DIFFERENTIATION
    Mitchell A Lazar; Fiscal Year: 2013
    ..Our innovative approach will elucidate mechanisms underlying target gene- and tissue-specificity of PPAR?, which can be translated to the design of more selective insulin sensitizers to combat the epidemic of metabolic disorders. ..
  16. Transcriptional and epigenomic control of adipose tissue development and function
    David J Steger; Fiscal Year: 2013
    ....
  17. Disruption of NAD/SIRT1-CLOCK Feedback Loop in Diabetes Pathophysiology
    ALISON HOLLEY AFFINATI; Fiscal Year: 2013
    ..These studies will further our understanding of the molecular mechanism underlying the interconnection between circadian rhythm and metabolism. ..
  18. Hepatic Fatty Acid Metabolism and Steatosis
    NICHOLAS DAVIDSON; Fiscal Year: 2013
    ..abstract_text> ..