Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat.
Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat.
复制标题
UTX和DNMT1之间的表观遗传相互作用调节饮食诱导的棕色脂肪的肌源性重构。
DOI：
10.1038/s41467-021-27141-7
复制
发表时间：
2021-11-25
影响因子：
16.6
通讯作者：
Xue B
中科院分区：
文献类型：
--
作者：
Li F;Jing J;Movahed M;Cui X;Cao Q;Wu R;Chen Z;Yu L;Pan Y;Shi H;Shi H;Xue B
棕色脂肪细胞与骨骼肌具有相同的发育起源。在这里，我们发现棕色脂肪细胞到肌细胞的重塑也存在于成熟的棕色脂肪细胞中，并且由长时间的高脂饮食（HFD）喂养诱导，导致棕色脂肪功能障碍。这一过程是由表观遗传途径的相互作用，涉及组蛋白和DNA甲基化。在成熟的棕色脂肪细胞中，组蛋白去甲基化酶UTX维持Prdm16启动子处抑制性标记H3K27me3的持续去甲基化，导致Prdm16的高表达。然后PRDM16将DNA甲基转移酶DNMT1募集到Myod1启动子，导致Myod1启动子超甲基化并抑制其表达。PRDM16和DNMT1之间的相互作用协调地用于维持棕色脂肪细胞的特性，同时抑制成熟棕色脂肪细胞中的肌源性重塑，从而促进其活跃的棕色脂肪细胞产热功能。通过HFD喂养抑制这种相互作用诱导棕色脂肪细胞到肌细胞的重塑，这限制了棕色脂肪细胞的产热能力并损害饮食诱导的产热，导致肥胖的发展。棕色脂肪细胞有助于能量平衡，脂肪细胞发育和棕色脂肪细胞产热部分受表观遗传修饰调节。在这里，作者报告说，组蛋白去甲基化酶Utx通过PRDM16的去甲基化来维持棕色脂肪细胞的身份，而PRDM16反过来又通过DNMT1介导的Myod1启动子超甲基化来抑制小鼠的肌源性重塑。
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. Brown adipocytes contribute to energy balance, and adipocyte development and brown adipocyte thermogenesis are in part regulated by epigenetic modifications. Here the authors report that the histone demethylase Utx maintains brown adipocyte identity via demethylation of PRDM16, which in turn represses myogenic remodelling via DNMT1-mediated Myod1 promoter hypermethylation in mice.