title: Histone Deacetylase 1 (HDAC1) Negatively Regulates Thermogenic Program in Brown Adipocytes via Coordinated Regulation of Histone H3 Lysine 27 (H3K27) Deacetylation and Methylation.
abstract: Inhibiting class I histone deacetylases (HDACs) increases energy expenditure, reduces adiposity, and improves insulin sensitivity in obese mice. However, the precise mechanism is poorly understood. Here, we demonstrate that HDAC1 is a negative regulator of the brown adipocyte thermogenic program. The Hdac1 level is lower in mouse brown fat (BAT) than white fat, is suppressed in mouse BAT during cold exposure or β3-adrenergic stimulation, and is down-regulated during brown adipocyte differentiation. Remarkably, overexpressing Hdac1 profoundly blocks, whereas deleting Hdac1 significantly enhances, β-adrenergic activation-induced BAT-specific gene expression in brown adipocytes. β-Adrenergic activation in brown adipocytes results in a dissociation of HDAC1 from promoters of BAT-specific genes, including uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor γ co-activator 1α (Pgc1α), leading to increased acetylation of histone H3 lysine 27 (H3K27), an epigenetic mark of gene activation. This is followed by dissociation of the polycomb repressive complexes, including the H3K27 methyltransferase enhancer of zeste homologue (EZH2), suppressor of zeste 12 (SUZ12), and ring finger protein 2 (RNF2) from (and concomitant recruitment of H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) to) Ucp1 and Pgc1α promoters, leading to decreased H3K27 trimethylation, a histone transcriptional repression mark. Thus, HDAC1 negatively regulates the brown adipocyte thermogenic program, and inhibiting Hdac1 promotes BAT-specific gene expression through a coordinated control of increased acetylation and decreased methylation of H3K27, thereby switching the transcriptional repressive state to the active state at the promoters of Ucp1 and Pgc1α. Targeting HDAC1 may be beneficial in prevention and treatment of obesity by enhancing BAT thermogenesis.
authors.affiliation: From the Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, Georgia 30303 and.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Li
authors.affiliation: From the Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, Georgia 30303 and.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: From the Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, Georgia 30303 and.
authors.forename: Xin
authors.initials: X
authors.lastname: Cui
authors.affiliation: From the Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, Georgia 30303 and.
authors.forename: Lin
authors.initials: L
authors.lastname: Zha
authors.affiliation: the Department of Animal and Avian Science, University of Maryland, College Park, Maryland 20742.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: From the Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, Georgia 30303 and hshi3@gsu.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: From the Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, Georgia 30303 and bxue@gsu.edu.
authors.forename: Bingzhong
authors.identifier: http://orcid.org/0000-0002-7857-1343
authors.initials: B
authors.lastname: Xue
mesh_terms: D000107:Acetylation / Q000187:drug effects; D052437:Adipocytes, Brown / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008815:Mice, Inbred Strains; D024101:Mitochondrial Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D063150:Polycomb Repressive Complex 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D022722:Thermogenesis / Q000187:drug effects; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D006657:Histones; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011994:Recombinant Proteins; C494163:Suz12 protein, mouse; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D008239:Lysine
keywords: H3K27; UCP1; brown adipocytes; epigenetics; histone deacetylase 1 (HDAC1); histone deacetylation; histone methylation; obesity; thermogenesis; uncoupling protein