Transcriptome analysis upon Nipbl, Brd2 and Brd4 knockdown in P19 cells
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ABSTRACT:
PROVIDER: PRJNA548966 | ENA |
REPOSITORIES: ENA
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Project description:Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin loading factor and has recently been associated with the BET (Bromodomains and Extra Terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. To understand the relationship between NIPBL and BET proteins, we have performed RNA-Seq expression analysis following depletion of the different proteins in mouse P19 teratocarcinoma cells. Results indicate that genes regulated by NIPBL largely overlap with those regulated by BRD4 but not with those regulated by BRD2.
2020-01-01 | GSE132785 | GEO
Project description:Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin loading factor and has recently been associated with the BET (Bromodomains and Extra Terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. We have study the genomic occupancy of NIPBL in mouse P19 teratocarcinoma cells.
2020-01-01 | GSE132784 | GEO
Project description:We analyzed the genome wide distributions of Brd2 and Brd4 in Th17 cells. We find that Brd2 and Brd4 have distinct genome-wide localization in Th17 cells, further experiments reveal tht Brd2 faciliates TF-complex formation in enhancers, enhancer-promoter interaction while Brd4 enhances transcriptional elongation.
2017-03-13 | GSE90788 | GEO
Project description:We analyzed the ChIP-seq data of Brd2 and Brd4 in Th17 cells. We find that Brd2 and Brd4 have distinct genome-wide deposition in Th17 cells, further experiments reveal tht Brd2 faciliates TF-complex formation in enhancers, enhancer-promoter interaction while Brd4 enhances transcriptional elongation.
2017-03-01 | GSE63778 | GEO
Project description:Natural killer cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a combined chemico-genetic approach, we have identified that BET bromodomains BRD2 and BRD4 are central regulators of NK cell responses. We show that both BRD2 and BRD4 play a key regulatory function in controlling NK cell specific inflammatory responses. However, knockdown of BRD2 but not BRD4 impairs NK cell cytolytic response, highlighting a redundant role for BRD4 in regulating NK cell killing. We further show that the prototypic monovalent BET inhibitor impairs in vitro NK cell mediated killing of cancer target cells, while the bivalent BET bromodomain AZD5153 does not. We ascribe these differences to the preferential affinity of JQ1(+) to BRD2, while AZD5153 has a higher affinity for BRD4. Our work suggests that inhibiting BET bromodomains may be an effective therapeutic strategy for controlling inflammatory function. Given that BRD2 but not BRD4 inhibition can impair NK cell mediated killing, our findings also have clinical significance in light of the ongoing clinical application of BET bromodomains in oncology.
2021-03-16 | GSE156423 | GEO
Project description:Genome occupancy of NIPBL in mouse P19 teratocarcinoma cells.
| PRJNA548964 | ENA
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:Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs. JQ1 (50-400 nM) increases insulin secretion from INS-1 cells in a concentration dependent manner. JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Overlapping yet discrete roles for individual BET proteins in metabolic regulation suggest new isoform-selective BET inhibitors may be useful to treat insulin resistant/diabetic patients. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.
2016-03-07 | GSE77450 | GEO
Project description:small RNA fractions were treated with either p19-WT or T111BpyAla to evaluate the catalytic ability of p19-T111BpyAla compared to the WT protein in degrading miRNAs
2023-04-28 | GSE229272 | GEO
Project description:The bromodomain and extra-terminal domain (BET) proteins are known as drug targets in diseases. However, the BET protein association profile to histone H4 hyperacetylation is not well understood and BET inhibition effects have been studied more in the context of BRD4 than BRD2. Here, by integrating chromatin and transcriptome analyses of ChIP-seq and Cap Analysis Gene Expression (CAGE) datasets, we show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding, only local changes of H4K5acK8ac were observed and surprisingly a remarkable number of BRD2-bound genes including MYC and its target genes were upregulated. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors (TFs) potentially involved in the JQ1 response in BRD2-dependent and independent manner.
2018-06-04 | GSE104481 | GEO