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Genome-wide BRD4, PolII and p65 occupancy as well as chromatin modifications in bone marrow derived macrophages from BRD4 conditional KO mice

ABSTRACT: We are reporting here genome wide distribution of BRD4 in bone marrow derived macrophages at steady state level and in reponse to LPS stimulation. In both condition, BRD4 distribution was found to be widespread in intragenic as well as intergenic regions with enrichment specifically near TSS. Characteristically BRD4 signal were highly enriched on enhancers of some active genes and hence were classified as BRD4 rich super-enhancers (>12kb long stretches). Super-enhancers are formed, in some instances by redistribution of BRD4 on LPS stimulated genes. BRD4 binding well correlated PolII binding at the chromatin acetylated at H3K27, H3K9 and H4tetraK. Interestingly many LPS induced BRD4 independent genes, despite BRD4 loss in the KO, maintained PolII binding at the chromatin enriched with acetylated lysines at H3K27, H3K9 and H4tetraK. Additionally among some BRD4 independent LPS inducible genes we detected stronger p65 enrichment in the KO. In contrast, P65 binding was not detected in BRD4 dependent genes. These observations provided evidence of plasticity of epigenetic changes in retaining inflammatory reponses in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE113226 | GEO | 2019/02/21

REPOSITORIES: GEO

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Bromodomain-Containing-Protein 4 (BRD4) Regulates RNA Polymerase II Serine 2 Phosphorylation in Human CD4+ T Cells

Project description:Transcriptional elongation by RNA polymerase II (Pol II) is regulated by positive transcription elongation factor b (P-TEFb) in association with Bromodomain-containing protein 4 (BRD4). We used genome-wide chromatin immunoprecipitation sequencing in primary human CD4+ T cells to reveal that BRD4 co-localizes with Ser2-phosphorylated Pol II (Pol II Ser2) at both enhancers and promoters of active genes. Disruption of bromodomain:histone acetylation interactions by JQ1, a small-molecule bromodomain inhibitor, resulted in decreased BRD4 binding, reduced Pol II Ser2, and reduced expression of lineage-specific genes in primary human CD4+ T cells. A large number of JQ1-disrupted BRD4 binding regions exhibited di-acetylated H4 (lysine-5 and -8) and H3K27 acetylation (H3K27ac), which correlated with the presence of histone acetyltransferases and deacetylases. Genes associated with BRD4/H3K27ac co-occupancy exhibited significantly higher activity than those associated with H3K27ac or BRD4 binding alone. Comparison of BRD4 binding in T cells and in human embryonic stem cells revealed that enhancer BRD4 binding sites were predominantly lineage-specific. Our findings suggest that BRD4-driven Pol II phosphorylation at serine 2 plays an important role in regulating lineage-specific gene transcription in human CD4+ T cells. Examination of BRD4, total Pol II, serine 2 phosphorylated Pol II and serine 5 phosphorylated Pol II binding in CD4+ T cells (with and without JQ1 treatment) and BRD4 binding in human embryonic stems cell; PolyA RNA expression in CD4+ T cells( with and without JQ1 treatment) using RNA-seq

2012-11-14 | E-GEOD-33281 | biostudies-arrayexpress

Bromodomain-Containing-Protein 4 (BRD4) Regulates RNA Polymerase II Serine 2 Phosphorylation in Human CD4+ T Cells

2012-11-14 | GSE33281 | GEO

BRD4 is necessary for epidermal differentiation

Project description:BRD4 is an epigenetic reader known to bind to acetylated lysines on histones and transcription factors, and it has been implicated in recruiting transcriptional machinery to promote differentiation gene expression in multiple cellular contexts. This activity is dependant on proper BRD4 localization to active promoters and enhancers, which is dependant on a variety of factors including lineage determining transcription factors (LDTFs). We found BRD4 to be necessary for epidermal differentiation, during which it shares many chromatin binding sites with a variety of epidermal lineage-determining transcription factors (LDTF's). BRD4 also regulates a similar differentiation related transcriptional program with the epidermal LDTF KLF4.

2020-04-03 | GSE140992 | GEO

BRD4 assists elongation of both coding and enhancer RNAs guided by histone acetylation

Project description:In serum-starved and re-fed mouse fibroblast, nascent RNA-seq analysis showed that the BET inhibitor JQ1 antagonized a process regulating PIC formation and a downstream process involved in progressive elongation. To specifically address the role of BRD4 and its interactions with acetylated histones and P-TEFb, YFP-tagged BRD4 proteins (wild type and mutant BRD4) were stably expressed in cells, endogenous BRD4 of which was knocked down by shRNA (shBRD4). Nascent RNA-seq analysis showed that BRD4 facilitated transcript elongation in a manner dependent on acetylated histone interaction but not P-TEFb. Furthermore, the role of BRD4 in enhancer activity was evaluated by mapping the intergenic distributions of Pol II, CDK9, H3K27 acetylation (Ac) and H4 Ac as well as BRD4 by ChIP-seq analysis. The results suggest that the role of intergenic BRD4 on nearby gene expression is mediated through enhanced synthesis of eRNA.

2014-11-10 | GSE58731 | GEO

Enhancer-binding of Brd4 controls cell differentiation

Project description:The epigenomic reader Brd4 is an important drug target for cancers. However, its role in cell differentiation and animal development remains largely unclear. Using two conditional knockout mouse strains and derived cells, we demonstrate that Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. Brd4 co-localizes with lineage-determining transcription factors (LDTFs) on active enhancers during differentiation. LDTFs coordinate with H3K4 mono-methyltransferases MLL3/MLL4 (KMT2C/KMT2D) and H3K27 acetyltransferases CBP/p300 to recruit Brd4 to enhancers activated during differentiation. Brd4 deletion prevents the enrichment of Mediator and RNA polymerase II transcription machinery, but not that of LDTFs, MLL3/MLL4-mediated H3K4me1, and CBP/p300-mediated H3K27ac, on enhancers. Consequently, Brd4 deletion prevents enhancer RNA production, cell identity gene induction and cell differentiation. Interestingly, Brd4 is dispensable for maintaining cell identity genes in differentiated cells. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction in differentiation.

2017-11-17 | GSE99101 | GEO

BRD4 dynamics reveal novel acrosome-dependent chromatin reorganization during post-meiotic mammalian sperm development

Project description:During the post-meiotic phase of spermatogenesis, transcription is progressively repressed as the nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyper-acetylation and replacement of most histones with sperm-specific protamines. Although BRDT has been shown to function in transcription as well as histone removal in post-meiotic spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of mouse testes revealed BRD4 in a complete ring around the nuclei of spermatids containing hyper-acetylated histones. The BRD4 ring lies directly adjacent to the acroplaxome, or the cytoskeletal base of the acrosome, and does not form in acrosomal mutant mice. ChIP sequencing in round spermatids revealed enrichment of BRD4 and acetylated histone H3 and H4 at the promoters of active genes. GO Term analysis showed that BRD4 and BRDT bind to distinct subsets of spermatogenesis-specific genes. Association of BRD4 with Cyclin T1 decreases as spermatogenesis progresses despite a persistence of association with acetylated H4. Moreover, acetylated histones are removed from the condensing spermatid nucleus in a wave following the progressing acrosome. These data provide evidence for an interesting mechanism in which BRD4 and perhaps acetylated histones are removed from the spermatid genome via the progressing acrosome as transcription is repressed. Single replicates each of Brd4, H3K9me3, H3K9ac, H4K5ac, H4K8ac, H4K12ac, H4K16ac, H4Kac (pan-acetyl antibody), and input in mouse round spermatid cells; input is used to control for local sonication efficiency bias.

2015-03-06 | E-GEOD-56526 | biostudies-arrayexpress

BRD4-chromatin interaction in reporter KBM7 cells (REDS15) with purine metabolism perturbation

Project description:To investigate whether BRD4-chromatin binding is modulated by purine levels, we performed BRD4 ChIP-seq in cells with SLC nucleoside transporters knockout, or cells with de novo purine synthesis inhibitor 6-MP treatment. (+)-JQ1, an inhibitor which disrupts BRD4 and acetylated histone binding, was used as a positive control.

2021-04-17 | GSE167374 | GEO

Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers is Suppressed by a MicroRNA [RNA-Seq]

Project description:BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3’ untranslated region of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression, and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.

2016-10-06 | GSE83228 | GEO

Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers is Suppressed by a MicroRNA [ChIP-Seq]

2016-10-06 | GSE82243 | GEO

: Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

Project description:BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4-dependent transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interact with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 enrichment at the hyper-acetylated chromatin regions. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 function and highlight targeting PRMT2/4 for better anti-tumor effect of BET inhibitors and DNA damaging agents.

2023-03-11 | PXD034650 | Pride

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