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BET bromodomain proteins regulate enhancer function during adipogenesis.

Significance 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... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 27, 2018, Vol.115(9), pp.2144-2149
Main Author: Brown, Jonathan D
Other Authors: Feldman, Zachary B , Doherty, Sean P , Reyes, Jaime M , Rahl, Peter B , Lin, Charles Y , Sheng, Quanhu , Duan, Qiong , Federation, Alexander J , Kung, Andrew L , Haldar, Saptarsi M , Young, Richard A , Plutzky, Jorge , Bradner, James E
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1711155115
Link: http://search.proquest.com/docview/2002483390/?pq-origsite=primo
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title: BET bromodomain proteins regulate enhancer function during adipogenesis.
format: Article
creator:
  • Brown, Jonathan D
  • Feldman, Zachary B
  • Doherty, Sean P
  • Reyes, Jaime M
  • Rahl, Peter B
  • Lin, Charles Y
  • Sheng, Quanhu
  • Duan, Qiong
  • Federation, Alexander J
  • Kung, Andrew L
  • Haldar, Saptarsi M
  • Young, Richard A
  • Plutzky, Jorge
  • Bradner, James E
subjects:
  • Adipocytes–Physiology
  • Adipogenesis–Cytology
  • Adipose Tissue–Physiology
  • Animals–Physiology
  • Cell Differentiation–Metabolism
  • Gene Expression Regulation–Metabolism
  • Male–Metabolism
  • Mice–Metabolism
  • Nuclear Proteins–Metabolism
  • Transcription Factors–Metabolism
  • Nuclear Proteins
  • Transcription Factors
  • Bet Bromodomain
  • Adipogenesis
  • Chromatin
  • Coactivator
  • Transcription
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 27, 2018, Vol.115(9), pp.2144-2149
description: Significance 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.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1711155115
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleBET bromodomain proteins regulate enhancer function during adipogenesis.
creatorBrown, Jonathan D ; Feldman, Zachary B ; Doherty, Sean P ; Reyes, Jaime M ; Rahl, Peter B ; Lin, Charles Y ; Sheng, Quanhu ; Duan, Qiong ; Federation, Alexander J ; Kung, Andrew L ; Haldar, Saptarsi M ; Young, Richard A ; Plutzky, Jorge ; Bradner, James E
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ispartofProceedings of the National Academy of Sciences of the United States of America, February 27, 2018, Vol.115(9), pp.2144-2149
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1711155115
subjectAdipocytes–Physiology ; Adipogenesis–Cytology ; Adipose Tissue–Physiology ; Animals–Physiology ; Cell Differentiation–Metabolism ; Gene Expression Regulation–Metabolism ; Male–Metabolism ; Mice–Metabolism ; Nuclear Proteins–Metabolism ; Transcription Factors–Metabolism ; Nuclear Proteins ; Transcription Factors ; Bet Bromodomain ; Adipogenesis ; Chromatin ; Coactivator ; Transcription
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descriptionSignificance 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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titleBET bromodomain proteins regulate enhancer function during adipogenesis.
authorBrown, Jonathan D ; Feldman, Zachary B ; Doherty, Sean P ; Reyes, Jaime M ; Rahl, Peter B ; Lin, Charles Y ; Sheng, Quanhu ; Duan, Qiong ; Federation, Alexander J ; Kung, Andrew L ; Haldar, Saptarsi M ; Young, Richard A ; Plutzky, Jorge ; Bradner, James E
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