title: The Histone Demethylase UTX Promotes Brown Adipocyte Thermogenic Program Via Coordinated Regulation of H3K27 Demethylation and Acetylation.
abstract: Brown adipocytes function to dissipate energy as heat through adaptive thermogenesis. Understanding the molecular mechanisms underlying the brown fat thermogenic program may provide insights for the development of therapeutic approaches in the treatment of obesity. Most studies investigating the mechanisms underlying brown fat development focus on genetic mechanisms; little is known about the epigenetic mechanisms in this process. We have discovered that ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), a histone demethylase for di- or tri-methylated histone 3 lysine 27 (H3K27me2/3), plays a potential role in regulating brown adipocyte thermogenic program. We found that UTX is up-regulated during brown adipocyte differentiation and by cold exposure in both brown adipose tissue (BAT) and white adipose tissue (WAT) of mice, suggesting a potential role in thermogenesis. Inactivation of UTX down-regulates brown fat specific gene expression, while overexpression of UTX does the opposite. Notably, activation of β adrenergic signaling recruits UTX to the UCP1 and PGC1α promoters, leading to decreased H3K27me3, a histone transcriptional repressive mark. UTX demethylates H3K27me3 and subsequently interacts with the histone acetyltransferase (HAT) protein CBP, resulting in increased H3K27 acetylation (H3K27ac), a histone transcriptional active mark. UTX positively regulate brown adipocyte thermogenic program through coordinated control of demethylating H3K27me3 and acetylating H3K27, switching the transcriptional repressive state to the transcriptional active state at the promoters of UCP1 and PGC1α. We conclude that UTX may play a potential role in regulation of brown adipocyte gene expression and may mediate β adrenergic activation of brown fat function.
authors: From the Department of Oncology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China, Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and.
authors: Lin
authors: L
authors: Zha
authors: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and.
authors: Fenfen
authors: F
authors: Li
authors: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and.
authors: Rui
authors: R
authors: Wu
authors: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and.
authors: Liana
authors: L
authors: Artinian
authors: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and.
authors: Vincent
authors: V
authors: Rehder
authors: Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland 20742.
authors: Liqing
authors: L
authors: Yu
authors: From the Department of Oncology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China, lianghoujie@sina.com.
authors: Houjie
authors: H
authors: Liang
authors: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and bxue@gsu.edu.
authors: Bingzhong
authors: B
authors: Xue
authors: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, and hshi3@gsu.edu.
authors: Hang
authors: H
authors: Shi
mesh_terms: D000107:Acetylation; D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003080:Cold Temperature; D000071221:Enhancer of Zeste Homolog 2 Protein; D015971:Gene Expression Regulation, Enzymologic; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics; D050356:Lipid Metabolism; D008239:Lysine / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008745:Methylation; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D022722:Thermogenesis; D014157:Transcription Factors / Q000235:genetics; D000071256:Uncoupling Protein 1
chemical_list: D006657:Histones; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C494163:Suz12 protein, mouse; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D056466:Histone Demethylases; C111778:Utx protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D050882:CREB-Binding Protein; D008239:Lysine
keywords: H3K27; UCP1; UTX; adipocyte; brown adipocytes; epigenetics; histone demethylase; obesity; uncoupling protein