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Systematic interaction profiling of human bromodomain-containing proteins reveals complex modes of binder recruitment for BET proteins

ABSTRACT: Systematic interaction profiling of human bromodomain-containing proteins reveals complex modes of binder recruitment for BET proteins

PROVIDER: PRJEB20389 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR1924252.fastq.gz	Fastqsanger.gz
	ERR1924253.fastq.gz	Fastqsanger.gz
	ERR1924254.fastq.gz	Fastqsanger.gz
	ERR1924255.fastq.gz	Fastqsanger.gz
	ERR1924256.fastq.gz	Fastqsanger.gz

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Systematic interaction profiling of human bromodomain-containing proteins reveals complex modes of binder recruitment for BET proteins

Project description:ChIP-seq of GFP tagged wild type and mutant human BRD3 in U-2 O3 cells

2018-04-01 | E-MTAB-5670 | biostudies-arrayexpress

BET bromodomain proteins regulate enhancer function during adipogenesis

Project description:BET bromodomain proteins regulate enhancer function during adipogenesis

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BET bromodomain proteins regulate enhancer function during adipogenesis

Project description:Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in expression of PPARg and C/EBPa, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARg and C/EBPa expression are less well characterized. Here we show the bromodomain-containing protein, BRD4, regulates transcription of PPARg and C/EBPa. 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. BET bromodomain inhibition 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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BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment

Project description:BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment

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BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [NET-seq]

Project description:Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation.

2017-09-18 | GSE79271 | GEO

BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [RNA-seq]

2017-09-18 | GSE79253 | GEO

BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [ChIP-seq]

2017-09-18 | GSE79288 | GEO

BET Bromodomain Proteins Regulate Transcriptional Reprogramming in Genetic Dilated Cardiomyopathy

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BET bromodomain inhibition

Project description:BET bromodomain inhibition

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BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.

Project description:Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy.

| S-EPMC5663500 | biostudies-literature

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