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

Fenfen Li,Liqing Yu,Huidong Shi,Jia Jing,Bingzhong Xue,Yi Pan,Rui Wu,Qiang Cao,Hang Shi,Ziyue Chen,Xin Cui,Miranda Movahed

doi:10.1038/s41467-021-27141-7

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.

Highlights

Brown adipocytes share the same developmental origin with skeletal muscle
We found that stimulation of BAT1 brown adipocytes with the β-adrenergic agonist isoproterenol significantly induced DNMT1 binding to Myod[1] promoter; whereas Prdm[16] knockdown in BAT1 brown adipocytes suppressed both basal- and isoproterenol-induced DNMT1 binding to Myod[1] promoter (Fig. 10A), suggesting that PRDM16 is required for the full ability of DNMT1 in maintaining DNA methylation at Myod[1] promoter in brown adipocytes
We have previously shown that the histone demethylase UTX promotes thermogenic program in brown adipocytes in vitro[13]; here we have determined the role of Utx in the regulation of brown fat thermogenesis and energy metabolism in vivo using genetic models and interrogated the underlying mechanism

Summary

Introduction

We find that a brown adipocyte-to-myocyte remodeling 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. We have further interrogated potential epigenetic mechanisms underlying Utx’s regulation of brown fat function during diet-induced obesity (DIO), and found that this process involves an interaction between histone and DNA methylation in the promoters of key molecules regulating brown or myogenic lineage determination, leading to a myogenic remodeling and thermogenic dysfunction in BAT of UTXKO mice during the development of DIO. We have identified that BAT-tomyocyte remodeling in BAT represents a common feature in DIO, which eventually leads to BAT dysfunction and contributes to the development of DIO

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Results

Conclusion