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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma.

ABSTRACT: Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma.

PROVIDER: PRJNA658688 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12495400_1.fastq.gz	Fastqsanger.gz
	SRR12495400_2.fastq.gz	Fastqsanger.gz
	SRR12495401.fastq.gz	Fastqsanger.gz
	SRR12495401_1.fastq.gz	Fastqsanger.gz
	SRR12495401_2.fastq.gz	Fastqsanger.gz

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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma [RNA-Seq]

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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma [ChIP-Seq]

Project description:Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma [ChIP-Seq]

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Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma.

Project description:Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors.

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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-08-25 | GSE156821 | GEO

Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma [ChIP-Seq]

Project description:We report the application of ChIP-seq for high-throughput profiling of histone mark H3K27ac in male and female mouse glioblastoma.

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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma [RNA-Seq]

Project description:We report the application of RNA-seq for high-throughput profiling of transcriptom in male and female mouse glioblastoma.

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Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release

Project description:Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.

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Toggling of BRD4 functions is triggered through its phosphorylation by JNK

Project description:BRD4 is a key regulatory factor in multiple cancers and cellular stress responses with pleotropic functions. BRD4 regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities, respectively. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that in response to a broad range of stimuli, this switch is mediated by the JNK kinase which directly interacts with BRD4. JNK specifically phosphorylates human BRD4 at Ser1117, Thr1186 and Thr1212, triggering transient BRD4 release from chromatin. JNK phosphorylation of BRD4 halts its HAT-mediated chromatin regulation and activates its transcription-enhancing kinase function. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. BRD4 release from chromatin augments its interaction with and phosphorylation of key transcriptional regulators RNA Pol II, PTEFb and c-MYC. The PP4 phosphatase dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which promotes its interaction with RNA Pol II at transcriptionally active sites. Accordingly, JNK-mediated release of BRD4 from chromatin leads to significantly elevated transcription of BRD4-regulated immune and inflammatory response genes through enhanced BRD4-Pol II interaction at the promoters of these genes. JNK phosphorylation of BRD4 occurs during T-cell activation and is required for epithelial to mesenchymal transition (EMT) in prostate cancer cells. These findings thus characterize a novel mechanism that triggers the transition of BRD4 from a chromatin regulator to transcriptional activator during stress/immune/inflammatory responses and EMT.

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