BRD4 marks chromatin on cell cycle genes activates their transcription and orchestrates mitotic cell division
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE153572 | GEO | 2022/01/31
REPOSITORIES: GEO
Similar Datasets
Project description:BRD4 marks chromatin on cell cycle genes activates their transcription and orchestrates mitotic cell division
| PRJNA643257 | ENA
Project description:BRD4 orchestrates genome folding to promote neural crest progenitor differentiation
| PRJNA716975 | ENA
Project description:On entry into mitosis, many transcription factors dissociate from chromatin, resulting in global transcriptional shutdown. During mitosis, some genes are marked to ensure the inheritance of their expression in the next generation of cells. The nature of mitotic gene marking, however, has been obscure. Brd4 is a double bromodomain protein that localizes to chromosomes during mitosis and is implicated in holding mitotic memory. In interphase, Brd4 interacts with P-TEFb and functions as a global transcriptional coactivator. We found that throughout mitosis, Brd4 remained bound to the transcription start sites of many M/G1 genes that are programmed to be expressed at the end of, or immediately after mitosis. In contrast, Brd4 did not bind to genes that are expressed at later phases of cell cycle. Brd4 binding to M/G1 genes increased at telophase, the end phase of mitosis, coinciding with increased acetylation of histone H3 and H4 in these genes. Increased Brd4 binding was accompanied by the recruitment of P-TEFb and de novo M/G1 gene transcription, the events impaired in Brd4 knockdown cells. In sum, Brd4 marks M/G1 genes for transcriptional memory during mitosis, and upon exiting mitosis, this mark acts as a signal for initiating their prompt transcription in daughter cells.
| S-EPMC2785733 | biostudies-literature
Project description:Higher-order chromatin structure is critical for proper gene regulation, but the relationship between genome folding and cellular identity remains elusive. Here, we show that genetic deletion of the Bromodomain-containing protein 4 (BRD4) in murine neural crest cells recapitulates features of cohesinopathies. We demonstrate that BRD4 interacts with NIPBL, a positive cohesin regulator, and acute depletion of BRD4 or loss of the BRD4-NIPBL interaction reduces NIPBL-occupancy, elucidating the importance of BRD4 in stabilizing NIPBL on chromatin. Genome-wide chromatin interaction mapping and quantitative imaging studies demonstrate that BRD4-depletion results in aberrant genome folding, specifically loss of a subset of chromatin loops, weakening of TADs, and compromised loop extrusion. Finally, loss of BRD4 or the interaction with NIPBL impedes neural crest differentiation which, remarkably, is rescued by WAPL depletion, a negative cohesin regulator. Our data reveal that BRD4 choreographs genome folding, illustrating the importance of balancing cohesin activity on progenitor differentiation.
2021-07-16 | GSE169516 | GEO
Project description:BRD4-NUT megadomains is an order of magnitude larger than super-enhancer regions and displays a more continuously enriched profile rather than appearing as a cluster of individual peaks. Chip-seq mapping of active chromatin marks in BRD4-NUT and different NMC cells
2015-07-14 | E-GEOD-70870 | biostudies-arrayexpress
Project description:Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns following mitosis. The acetyl-lysine binding protein BRD4 has been previously suggested to function as a transcriptional “bookmark” on mitotic chromatin. Here, genome-wide location analysis of BRD4 in erythroid cells, combined with novel data normalization and peak characterization approaches, reveals that BRD4 widely occupies mitotic chromatin. However, removal of BRD4 from mitotic chromatin does not impair post-mitotic activation of transcription. Additionally, histone mass spectrometry reveals global preservation of most posttranslational modifications (PTMs) during mitosis. In particular, H3K14ac, H3K27ac, H3K122ac, and H4K16ac widely mark mitotic chromatin, especially at lineage-specific genes, and predict BRD4 mitotic binding genome wide. Therefore, BRD4 is likely not a mitotic bookmark but only a “passenger”. Instead, mitotic histone acetylation patterns may constitute the actual bookmarks that restore lineage-specific transcription patterns after mitosis.
2019-04-10 | GSE128161 | GEO
Project description:Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns following mitosis. The acetyl-lysine binding protein BRD4 has been previously suggested to function as a transcriptional “bookmark” on mitotic chromatin. Here, genome-wide location analysis of BRD4 in erythroid cells, combined with novel data normalization and peak characterization approaches, reveals that BRD4 widely occupies mitotic chromatin. However, removal of BRD4 from mitotic chromatin does not impair post-mitotic activation of transcription. Additionally, histone mass spectrometry reveals global preservation of most posttranslational modifications (PTMs) during mitosis. In particular, H3K14ac, H3K27ac, H3K122ac, and H4K16ac widely mark mitotic chromatin, especially at lineage-specific genes, and predict BRD4 mitotic binding genome wide. Therefore, BRD4 is likely not a mitotic bookmark but only a “passenger”. Instead, mitotic histone acetylation patterns may constitute the actual bookmarks that restore lineage-specific transcription patterns after mitosis.
2019-04-10 | GSE128150 | GEO
Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 among a small number of candidates associated with BRD4-NUT in NMC patient cells but not present in 293T cells.
2017-04-05 | PXD005786 | Pride
Project description:Analysis of BRD4 ChIP-seq data of two types of human transformed fibroblasts (WT and HGPS) to identify specific and common binding sites for BRD4. Transformed cell lines were obtained by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S) of primary skin fibroblasts for HGPS patients (TRS-HGPS) and age-matched control wild-type individuals (TRS-WT) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. Examination of BRD4 binding events in TRS-WT and TRS-HGPS fibroblasts (2 independent cell lines in each group)
2014-10-02 | E-GEOD-61325 | biostudies-arrayexpress
Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.
2019-04-04 | PXD012715 | Pride