Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat

Fenfen Li, Jia Jing, Miranda Movahed, Xin Cui, Qiang Cao, Rui Wu, Ziyue Chen, Liqing Yu, Yi Pan, Huidong Shi, Hang Shi () and Bingzhong Xue ()
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Fenfen Li: Georgia State University
Jia Jing: Georgia State University
Miranda Movahed: Georgia State University
Xin Cui: Georgia State University
Qiang Cao: Georgia State University
Rui Wu: Georgia State University
Ziyue Chen: Georgia State University
Liqing Yu: University of Maryland School of Medicine
Yi Pan: Georgia State University
Huidong Shi: Medical College of Georgia, Augusta University
Hang Shi: Georgia State University
Bingzhong Xue: Georgia State University

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: Abstract Brown adipocytes share the same developmental origin with skeletal muscle. Here we find that a brown adipocyte-to-myocyte remodeling also exists in mature brown adipocytes, and is induced by prolonged high fat diet (HFD) feeding, leading to brown fat dysfunction. This process is regulated by the interaction of epigenetic pathways involving histone and DNA methylation. In mature brown adipocytes, the histone demethylase UTX maintains persistent demethylation of the repressive mark H3K27me3 at Prdm16 promoter, leading to high Prdm16 expression. PRDM16 then recruits DNA methyltransferase DNMT1 to Myod1 promoter, causing Myod1 promoter hypermethylation and suppressing its expression. The interaction between PRDM16 and DNMT1 coordinately serves to maintain brown adipocyte identity while repressing myogenic remodeling in mature brown adipocytes, thus promoting their active brown adipocyte thermogenic function. Suppressing this interaction by HFD feeding induces brown adipocyte-to-myocyte remodeling, which limits brown adipocyte thermogenic capacity and compromises diet-induced thermogenesis, leading to the development of obesity.

Date: 2021
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DOI: 10.1038/s41467-021-27141-7

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