The Histone Demethylase UTX Promotes Brown Adipocyte Thermogenic Program Via Coordinated Regulation of H3K27 Demethylation and Acetylation

J Biol Chem. 2015 Oct 9;290(41):25151-63. doi: 10.1074/jbc.M115.662650. Epub 2015 Aug 25.

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.

Keywords: H3K27; UCP1; UTX; adipocyte; brown adipocytes; epigenetics; histone demethylase; obesity; uncoupling protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adipocytes, Brown / cytology
  • Adipocytes, Brown / metabolism*
  • Animals
  • CREB-Binding Protein / metabolism
  • Cell Differentiation
  • Cell Line
  • Cold Temperature
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Expression Regulation, Enzymologic
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism*
  • Histones / chemistry*
  • Histones / metabolism*
  • Ion Channels / genetics
  • Lipid Metabolism
  • Lysine / metabolism*
  • Male
  • Membrane Potential, Mitochondrial
  • Methylation
  • Mice
  • Mitochondrial Proteins / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polycomb Repressive Complex 2 / metabolism
  • Promoter Regions, Genetic / genetics
  • Thermogenesis*
  • Transcription Factors / genetics
  • Uncoupling Protein 1

Substances

  • Histones
  • Ion Channels
  • Mitochondrial Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Suz12 protein, mouse
  • Transcription Factors
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Histone Demethylases
  • Utx protein, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2
  • CREB-Binding Protein
  • Lysine