KMT5c modulates adipocyte thermogenesis by regulating Trp53 expression
KMT5c modulates adipocyte thermogenesis by regulating Trp53 expression
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DOI：
10.1073/pnas.1922548117
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发表时间：
2020-08
期刊：
影响因子：
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通讯作者：
Qingwen Zhao;Zhe Zhang;Weiqiong Rong;Weiwei Jin;Linyu Yan;Wenfang Jin;Yingjiang Xu;Xuan Cui;Q. Tang;Dongning Pan
中科院分区：
文献类型：
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作者：
Qingwen Zhao;Zhe Zhang;Weiqiong Rong;Weiwei Jin;Linyu Yan;Wenfang Jin;Yingjiang Xu;Xuan Cui;Q. Tang;Dongning Pan
意义脂肪细胞的产热功能依赖于产热程序的激活，该程序由一系列独特的转录和表观遗传调节因子协调调节。组蛋白甲基化在组织特异性基因表达的建立中是一种重要的表观遗传调控模式。然而，H4K20甲基化在产热脂肪细胞中的作用尚未完全阐明。我们的论文揭示了Kmt5c参与调节脂肪组织的产热程序。脂肪细胞特异性Kmt5c KO小鼠表现出产热基因的表达降低，并且容易发生饮食诱导的肥胖。这些发现表明，激活KMT5c的甲基转移酶活性可能是代谢性疾病的潜在策略。棕色和米色脂肪细胞具有产热能力，以适应环境热或营养变化。组蛋白甲基化是一种重要的表观遗传修饰，参与了脂肪细胞非寒颤产热的调节。在这里，我们描述了一个由KMT5c（一种H4K20甲基转移酶）领导的分子网络，它调节脂肪细胞产热和全身能量消耗。在棕色和米色脂肪细胞中，β3-肾上腺素能信号级联可显著诱导Kmt5c的表达。体内脂肪细胞中Kmt5c的消耗导致棕色和皮下脂肪组织中产热基因的表达减少。这些小鼠容易发生高脂肪饮食引起的肥胖，并产生葡萄糖耐受不良。Kmt5c敲除（KO）小鼠中转化相关蛋白53 （Trp53）的表达增强，这是由于其近端启动子上抑制标记H4K20me3的减少，导致代谢表型。总之，这些发现揭示了kmt5c介导的H4K20甲基化在维持和激活脂肪细胞产热程序中的生理作用。
Significance The thermogenic function of adipocytes relies on the activation of the thermogenic program that is coordinately modulated by an array of unique transcriptional and epigenetic regulators. Histone methylations represent an essential epigenetic mode of regulation in the establishment of tissue-specific gene expression. However, the role of H4K20 methylation in thermogenic adipocytes is not completely elucidated. Our paper revealed Kmt5c is involved in regulating the thermogenic program in adipose tissues. Adipocyte-specific Kmt5c KO mice demonstrate decreased expression of thermogenic genes and are prone to diet-induced obesity. The findings indicate that activation of methyltransferase activity of KMT5c might be a potential strategy for metabolic diseases. Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a β3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.