Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity

• Published in: Developmental cell Vol. 35; no. 5; pp. 568 - 583
• Main Authors: Pan, Dongning, Huang, Lei, Zhu, Lihua J., Zou, Tie, Ou, Jianhong, Zhou, William, Wang, Yong-Xu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2015
• Subjects: Adipocytes - cytology; Adipocytes - metabolism; Adipose Tissue, Brown - embryology; Adipose Tissue, White - embryology; Animals; Apoptosis Regulatory Proteins - metabolism; Body Weight; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Developmental; Ion Channels - metabolism; Jumonji Domain-Containing Histone Demethylases - metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins - metabolism; Point Mutation; Promoter Regions, Genetic; Sequence Analysis, RNA; Thermogenesis - genetics; Transcription Factors - metabolism; Transgenes; Uncoupling Protein 1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2015.11.002

Progression from brown preadipocytes to adipocytes engages two transcriptional programs: the expression of adipogenic genes common to both brown fat (BAT) and white fat (WAT), and the expression of BAT-selective genes. However, the dynamics of chromatin states and epigenetic enzymes involved remain poorly understood. Here we show that BAT development is selectively marked and guided by repressive H3K27me3 and is executed by its demethylase Jmjd3. We find that a significant subset of BAT-selective genes, but not common fat genes or WAT-selective genes, are demarcated by H3K27me3 in both brown and white preadipocytes. Jmjd3-catalyzed removal of H3K27me3, in part through Rreb1-mediated recruitment, is required for expression of BAT-selective genes and for development of beige adipocytes both in vitro and in vivo. Moreover, gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight reduction and cold intolerance, respectively. Together, we identify an epigenetic mechanism governing BAT fate determination and WAT plasticity. •H3K27me3 marks BAT genes, but not common fat genes or WAT genes, in preadipocytes•Demethylation by Jmjd3 is required for BAT gene expression and browning of WAT•Rreb1 regulates Ucp1 and Cidea expression by recruiting Jmjd3 to their promoters•Jmjd3 regulates age-dependent body weight gain and cold intolerance in mice Pan, Huang et al. show that H3K27me3 demarcates brown-fat-selective genes, but spares common-fat- and white-fat-selective genes, in preadipocytes. Jmjd3-catalyzed erasure of H3K27me3 is required for brown fat gene expression and browning of white fat. Gain- and loss-of-function Jmjd3 transgenic mice show body weight reduction and cold intolerance, respectively.