BET bromodomain proteins regulate enhancer function during adipogenesis.
BET bromodomain proteins regulate enhancer function during adipogenesis.
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DOI：
10.1073/pnas.1711155115
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发表时间：
2018-02-27
影响因子：
11.1
通讯作者：
Bradner JE
中科院分区：
文献类型：
--
作者：
Brown JD;Feldman ZB;Doherty SP;Reyes JM;Rahl PB;Lin CY;Sheng Q;Duan Q;Federation AJ;Kung AL;Haldar SM;Young RA;Plutzky J;Bradner JE
脂肪细胞分化是维持代谢稳态所必需的。转录因子通过调节脂肪细胞功能所需基因的表达来控制脂肪细胞的分化。本研究表明，含溴结构域蛋白的溴结构域和外结构域（BET）家族是脂肪形成的重要协同调节因子。BRD4与驱动PPARγ表达的增强子结合，PPARγ是正常脂肪细胞分化所需的主转录因子。破坏这些增强子上的BRD4会阻断PPARγ的表达并损害分化。了解PPARγ表达和脂肪细胞分化的分子决定因素可能有助于了解与脂肪组织功能障碍和肥胖相关的代谢性疾病的发病机制。此外，这些数据表明代谢途径及其转录调控因子是BET溴域抑制剂的潜在靶点，目前正在癌症治疗的人类临床试验中进行研究。发育转变是由主调控转录因子引导的。在脂肪形成过程中，转录级联在PPARγ和C/EBPα的表达中达到高潮，它们协调了脂肪细胞基因表达程序的激活。然而，控制PPARγ和C/EBPα表达的共激活因子尚未被很好地表征。在这里，我们发现含有溴结构域的蛋白BRD4调节PPARγ和C/EBPα的转录。对BRD4染色质占用率的分析表明，在3T3L1成纤维细胞中诱导脂肪形成会促使BRD4动态重新分布到靠近控制脂肪细胞分化的基因的新生超增强子。抑制含溴结构域和外结构域（BET）家族的蛋白会阻碍BRD4在这些新生增强子上的占据，并破坏Pparg和Cebpa的转录，从而阻断脂肪形成。此外，CRISPRi沉默了这些brd4占据的Pparg位点远端调控元件，表明这些增强子在3t3l1中控制Pparg基因表达和脂肪形成中起着关键作用。总之，这些数据确定了BET溴结构域蛋白是脂肪细胞状态转变的时间和环境依赖的共激活因子。
Adipocyte differentiation is necessary for metabolic homeostasis. Transcription factors control adipocyte differentiation by regulating expression of genes required for adipocyte function. Here we show that the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins are important coregulators of adipogenesis. BRD4 binds to enhancers that drive expression of PPARγ, a master transcription factor required for normal adipocyte differentiation. Disrupting BRD4 at these enhancers blocks PPARγ expression and impairs differentiation. Understanding the molecular determinants of PPARγ expression and adipocyte differentiation may provide insights into the pathogenesis of metabolic diseases related to adipose tissue dysfunction and obesity. Furthermore, these data implicate metabolic pathways and their transcriptional regulators as potential targets of BET bromodomain inhibitors, as currently under investigation in human clinical trials of cancer therapy. Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.
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影响因子：
64.5
作者：
Long, Hannah K.;Prescott, Sara L.;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
11.2
作者：
Picaud S;Da Costa D;Thanasopoulou A;Filippakopoulos P;Fish PV;Philpott M;Fedorov O;Brennan P;Bunnage ME;Owen DR;Bradner JE;Taniere P;O'Sullivan B;Müller S;Schwaller J;Stankovic T;Knapp S
通讯作者：
Knapp S
影响因子：
7
作者：
Saint-André V;Federation AJ;Lin CY;Abraham BJ;Reddy J;Lee TI;Bradner JE;Young RA
通讯作者：
Young RA
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16
作者：
Roe, Jae-Seok;Mercan, Fatih;Rivera, Keith;Pappin, Darryl J.;Vakoc, Christopher R.
通讯作者：
Vakoc, Christopher R.