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

ABSTRACT: We report the application of Calling Card sequencing technology for high-throughput profiling of Brd4-bound enhancers in male and female mouse glioblastoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE156678 | GEO | 2020/08/23

REPOSITORIES: GEO

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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.

| S-EPMC8072233 | biostudies-literature

Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

Project description:Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

| PRJNA659250 | ENA

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

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

| PRJNA658688 | ENA

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.

2020-08-26 | GSE156820 | GEO

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.

2020-08-26 | GSE156819 | GEO

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

Project description: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]

| PRJNA659378 | ENA

Binding and regulation of transcription by yeast Ste12 variants to drive mating and invasion phenotypes

Project description:Here, we examine how six single amino acid variants in the DNA-binding domain of Ste12 – a yeast transcription factor regulating mating and invasion – alter Ste12 genome binding, motif recognition and gene expression to yield markedly different phenotypes. Using a combination of the calling card method, RNA sequencing , we find that variants with dissimilar binding and expression profiles can converge onto similar cellular behaviors.

2020-01-30 | GSE141713 | GEO

Intrinsic histone acetyltransferase activity of BRD4 is responsible for nucleosome eviction and transcriptional activation

Project description:Purpose: BRD4 is a chromatin reader and transcriptional activator of M/G1 genes.We discovered that BRD4 is a novel histone acetyltransferase that acetylates histones and evicts nucleosomes. Here, investigated genome-wide changes in nucleosome occupancy and transcription caused by BRD4 HAT activity . Method: Human U2OS cells were transfected with either wild type BRD4 (WT), a BRD4 HAT mutant (MT) or a empty vector (NT) in biological duplicates, harvested 18 hrs post transfection and subjected to global MNase-seq and RNA-seq analysis. Results: The results show that while wild type BRD4 reduces nucleosome occupancy and increases transcription genome-wide, the BRD4 HAT mutant does not. Conclusion: BRD4 HAT activity is responsible for evicting nucleosomes and activating transcription.

2016-05-08 | GSE71577 | GEO

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