Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis
Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis
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DOI：
10.1101/2023.06.27.546683
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发表时间：
2023-07
期刊：
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通讯作者：
I. Sandovici;Borbála Mifsud;A. Emery;P. Gulati;K. Kentistou;A. Banu;Niamh Campbell;B. Hardwick
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文献类型：
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作者：
I. Sandovici;Borbála Mifsud;A. Emery;P. Gulati;K. Kentistou;A. Banu;Niamh Campbell;B. Hardwick
脂肪发生是一个多步骤的过程，表观遗传机制和动态3D染色质折叠被认为起着重要的调节作用。然而，在后期脂肪形成的动力学和功能作用的启动子接触是未知的。在这里，使用多组学方法，我们发现了启动子开关和广泛的启动子接触的3D重新布线的证据，以及转录组和表观基因组在后期脂肪形成中的变化。我们确定了几个集群的启动子接触与独特的时间配置文件表明远端增强子的关键作用。通过整合转录组学，启动子捕获Hi-C和可药用基因的siRNA筛选，我们确定了19种新的晚期脂肪形成调节因子，其中一半以上具有肽酶或泛素蛋白连接酶活性。基于群体的遗传分析表明，19个基因中的3个（LAP 3，CELA 1和GPR 157）参与了人类肥胖的调节。这些发现为后期脂肪形成的表观遗传调控提供了新的线索，推进了我们对功能性脂肪细胞形成机制的理解，并确定了预防/治疗肥胖和相关疾病的潜在靶点。
Adipogenesis is a multi-step process, with epigenetic mechanisms and dynamic 3D chromatin folding thought to play important regulatory roles. However, the kinetics and functional roles of promoter contacts during late-stage adipogenesis are unknown. Here, using multi-omics approaches, we found evidence for promoter switching and widespread 3D rewiring of promoter contacts, as well as changes in the transcriptome and epigenome in late-stage adipogenesis. We identified several clusters of promoter contacts with unique temporal profiles suggesting crucial roles for distal enhancers. By integrating transcriptomics, promoter-capture Hi-C and a siRNA screen of druggable genes, we identified 19 novel regulators of late-stage adipogenesis, over half of which have peptidase or ubiquitin-protein ligase activities. Population-based genetic analyses showed that three of the 19 genes (LAP3, CELA1 and GPR157) are involved in regulation of adiposity in humans. These findings shed new light on the epigenetic regulation of late-stage adipogenesis, advancing our understanding of the mechanisms that underpin the formation of functional adipocytes and identifying potential targets for preventing/treating obesity and related disorders.