ChIP-Seq of H4K5acK8ac in GM12878, K562
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113635 | GEO | 2018/06/04
REPOSITORIES: GEO
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Project description:The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. 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. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.
2018-06-04 | GSE113711 | 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
Project description:The bromodomain and extra-terminal domain (BET) family consists of acetyllysine-binding proteins involved in many cancers, including glioblastoma multiforme. While the BET family activates transcription through binding to hyperacetylated histone H4 with simultaneous acetylation of K5 and K8 (H4K5acK8ac), so far epigenomic analysis of the BET family has mainly focused on H3K27ac, which is not their binding target. Here, we have examined the epigenomic profiles, including H4K5acK8ac and a BET family protein, BRD4, along with transcriptomics using a BET inhibitor, JQ1, in three human glial cell lines. We found that the expression of genes in which H4K5acK8ac is preferred over H3K27ac at promoters was mostly downregulated upon JQ1 in a glioblastoma stem cell (GSC) line. Knockdown of genes with the H4K5acK8ac-preferred promoters diminished the stemness of GSC. By defining super-enhancers (SEs) ranked by H4K5acK8ac, we found that 43% of the H4K5acK8ac-ranked SE were different from H3K27ac-ranked SE in GSC. CRISPR-Cas9-mediated deletion of the H4K5acK8ac-preferred SEs reduced the expression of associated genes including MYCN and NFIC in GSC and diminished its stemness. These results validate a novel strategy to identify genes involved in the regulation of glioblastoma stemness, through histone H4 hyperacetylation.
2023-07-23 | GSE178471 | GEO
Project description:Changes in acetylation of histone H4 are a common hallmark of cancer cells. In leukemia cells, histone H4 is characterized by loss of K16 mono-acetylation. Bromodomain proteins specifically recognize acetylated lysines and have been used as a target for anti cancer drug, JQ1 and iBET. Although acetylation and de-acetylation of histone H4 have been shown to have big impact in cancer cells, little attention has been focused on histone H4-acetylation at a genome level. To uncover potential epigenetic role of hyper-acetylated histone H4 at a genome-wide level in cancer cell, we generated a novel monoclonal antibody specifically recognizing histone H4 with at least two acetylated lysine residues (H4K5ac+K8ac). At the genome-wide level, hyper-acetylated histone H4 is associated with promoter and regulatory element (active enhancer, eRNA and super enhancer). We show that diacetylation at K5 and K8 of histone H4 co-localizes H3K27ac and BRD2 in the majority of active enhancer and promoters. However BRD2 has a stronger association with H4K5acK8ac. Furthermore we identified two specific chromatin states, which separately contain either H3K27ac or acetylated histone H4. Although JQ1 led to global reduction of BRD2 binding on the chromatin, only local changes of histone H4 multi-acetylation were observed upon BET inhibition by JQ1
2018-06-04 | GSE113714 | GEO
Project description:Newly discovered histone lysine acylations increase the functional diversity of nucleosomes well beyond acetylation. Here, we focus on histone butyrylation in the context of sperm cell differentiation. Specifically, we investigate the butyrylation of histone H4 lysine 5 and 8 at gene promoters, where acetylation guides the binding of Brdt, a bromodomain-and-extra-terminal protein, thereby mediating stage-specific gene expression programs. Genome-wide mapping data show that highly active Brdt-bound gene promoters systematically harbour competing histone acetylation and butyrylation marks at H4 K5 and K8. Histone butyrylation, despite acting as a direct stimulator of transcription, competes with acetylation, especially at H4 K5, to prevent Brdt binding. The observed in vivo H4 K5K8 acetylation butyrylation state at active promoters is reproduced in vitro where p300 indistinctly acetylates and butyrylates H4 K5 and K8. Altogether, highly active gene promoter regions are characterized by alternating H4 acetylation and butyrylation sustaining direct gene activation and a dynamic bromodomain binding.
2016-07-13 | GSE77277 | 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:BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co‑regulators. BET proteins bind to acetylated lysines in the histones of nucleosomal chromatin and function either as co‑activators or co‑repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that BET inhibitor (JQ1) treatment of BET protein interactions with hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes and survival of key inflammatory drivers, alveolar macrophages (AM) in COPD. Transcriptome analysis of AM from COPD patients indicated up-regulation of macrophage type 1 genes upon LPS stimulation. BET inhibitor JQ1 treatment attenuated expression of multiple genes, including pro-inflammatory cytokines and regulators innate and adaptive immune cells. We demonstrated for the first time that JQ1 regulates differentially LPS-induced cytokine release from AM or peripheral blood mononuclear cells (PBMC) of COPD patients than PBMC of healthy controls. Using BET regulated gene signature, we identified a subset of COPD patients, which we propose to benefit from BET inhibition. This work demonstrates that the effects of BET inhibition through JQ1 treatment of inflammatory cells has the potential to restore gene expression dysregulated in COPD patients vs healthy controls, and the expression of BET regulated genes is altered in COPD. The findings provide evidence of histone hyperacetylation as a mechanism driving chronic inflammatory changes in COPD.
2017-03-02 | GSE92532 | GEO
Project description:In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), NF-kappaB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IkappaB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-kappaB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling. For JQ1 time course gene expression profiling, HBL1 and LP1 cells were treated with either DMSO or 100nM JQ1 for 1h, 3h, 8h, and 24h. For shRNA gene expression profiling, HBL1 cells were infected with either a Ctrl shRNA or with shRNA targeting BRD2 or BRD4. Following puromycin selection, shRNA expression was induced for 1 day and 2 days.
2014-08-01 | E-GEOD-58791 | biostudies-arrayexpress
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors
2014-04-25 | E-GEOD-55062 | biostudies-arrayexpress
Project description:Transcription factor GATA1 binding in erythroblasts in the presence and absence of BET inhibitor JQ1, and BET protein BRD3 and BRD4 binding in erythroblasts in the presence and absence of GATA1. Inhibitors of Bromodomain and Extra-Terminal motif proteins (BETs) are being evaluated for the treatment of cancer and other diseases yet their physiologic mechanisms remain largely unknown. We used genomic and genetic approaches to examine BET function in a hematopoietic maturation system driven by GATA1, an acetylated transcription factor previously shown to interact with BETs. We found that while BRD3 occupied the majority of GATA1 binding sites, BRD2 and BRD4 were also recruited to a subset of GATA1-occupied sites. Functionally, BET inhibition impaired GATA1-mediated transcriptional activation, but not repression, genome-wide. Co-activation by BETs was accomplished both by facilitating genomic occupancy of GATA1 and subsequently supporting transcription activation. Using a combination of CRISPR/CAS9-mediated genomic engineering and shRNA approaches we observed that depletion of either BRD2 or BRD4 alone blunted erythroid gene activation, while depletion of BRD3 only affected erythroid transcription in the setting of BRD2 deficiency. These results suggest that pharmacologic BET inhibition should be interpreted in the context of distinct steps in transcriptional activation and partially overlapping functions among BET family members. GATA1 null erythroblasts (G1E) conditionally expressing GATA1 as a GATA1-ER fusion protein were induced to express GATA1 by addition of 100nM estradiol for 24 hours. For GATA1 binding experiments this occurred in the absence or presence of 250nM JQ1. For BRD3 and BRD4 occupancy experiments G1E cells were compared to G1E cells with activated GATA1-ER fusion protein.
2015-02-23 | E-GEOD-62736 | biostudies-arrayexpress