Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

HDAC inhibitors result in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

ABSTRACT: Histone acetylation is associated with active transcription and serves as a binding site for reader proteins that function in transcriptional initiation and elongation. Histone acetylation levels are regulated through the actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) that antagonistically control the overall balance of this posttranslational modification. HDAC inhibitors (HDACi) are potent agents that disrupt this balance and are used clinically to treat a range of human diseases including cancer. Despite their clinical applications, little is known about their chromatin effects. By applying quantitative genomic and proteomic approaches, we demonstrate that HDACi robustly increase a low abundance histone acetylation state (H4 K5ac/K8ac/12ac/K16ac), which serves as a preferred binding substrate for a variety of human bromodomain-containing proteins, including BRD4. This H4 polyacetylation signature observed after HDACi treatment accumulates in the transcribed regions of genes and correlates with the targeting of BRD4 to genes with increased gene expression. Collectively, these results suggest that HDAC inhibition functions, at least in part, through expansion of a rare chromatin acetylation state, which then retargets lysine-acetyl reader proteins associated with changes in gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159620 | GEO | 2020/10/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

How basic nuclear processes are affected by selected HAT and HDAC inhibitors - Signalling pathways affected by HATs/HDACs inhibitor

Project description:Balance between histone acetylation and deacetylation is fundamental for proper gene function, thus knowledge of how to modulate these epigenetic processes is important for understanding of nuclear events, including replication, transcription, splicing and DNA repair. Here, we have studied an effect of HDAC inhibitor, SAHA, and we compared it with an effect of natural product, derivative of anacardic acid (MG149). Recently, it was discovered that MG149 has inhibitory potential for HATs' activity on histone H3 and H4 when tested on nuclear extracts.

2014-01-20 | E-MTAB-1481 | biostudies-arrayexpress

HDAC3 requirement for the inflammatory gene expression program in macrophages [ChIP_Seq]

Project description:Pan-Hdac inhibitors (HDACi) are endowed with a potent anti-inflammatory activity, but the relative role of each of the eleven Hdac proteins sensitive to HDACi to the inflammatory gene expression program is unknown. Using an integrated genomic approach we found that Hdac3-deficient macrophages are unable to activate almost half of the inflammatory gene expression program when stimulated with lipopolysaccharide (LPS). A large part of the activation defect is due to loss of basal and LPS-inducible expression of IFNb, which in basal cells maintains Stat1 protein levels, and after stimulation acts in an autocrine/paracrine manner to promote a secondary wave of Stat1-dependent gene expression. We show that loss of Hdac3-mediated repression of nuclear receptors leads to hyperacetylation of thousands of genomic sites and associated gene derepression. The upregulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), has a causative role in the phenotype, since its chemical inhibition reverts the Ifnb activation defect. These data may have relevance for the use of selective Hdac inhibitors as anti-inflammatory agents. Chromatin immuno-precipitations of H4 histone pan-acetylation followed by multiparallel sequencing performed in murine bone marrow-derive macrophages. Experiments carried out in untreated cells as well as in cells treated for 4hrs with lipopolysaccharide (LPS), for both HDAC3 +/- (wt) and HDAC3 -/- (KO) mice.

2012-07-08 | E-GEOD-33163 | biostudies-arrayexpress

Mus musculus

Project description:Histone H4 acetylation and epigenetic reader Brd4 are critial regulators of pluripotency in embryonic stem cells

| PRJNA308546 | ENA

Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

Project description:Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we apply an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observe hyper-acetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrate that the bromodomain and extraterminal (BET) protein, BRD4, is a bona fide ‘reader’ of H2A.Z acetylation, and further provide evidence that BET family protein inhibition ameliorates transcriptional abnormalities in patient-derived neurons. Thus, treatments aimed at alleviating BET protein interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.

2022-05-06 | PXD031767 | Pride

Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BRD4 in schizophrenia

Project description:Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we applied an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observed hyper-acetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrated that the bromodomain containing protein, BRD4, is a bona fide ‘reader’ of H2A.Z acetylation, and further provide evidence that BRD4 inhibition ameliorates transcriptional abnormalities in patient-derived neurons and improves sensorimotor gating behavior in mice. Thus, treatments aimed at alleviating BRD4 interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.

2022-01-12 | GSE144639 | GEO

Acetylated Histone Reader Brd4 functions as Repair Adaptor in Immunoglobulin Class Switch Recombination

Project description:Class Switch Recombination (CSR) is a B cell specific genomic alteration induced by activation induced cytidine deaminase (AID)-dependent DNA break, followed by repair and recombination at the immunoglobulin heavy-chain locus. The involvement of several chromatin-associated factors in promoting AID-induced DNA break formation has been reported. However, the involvement of chromatin adaptors at the repair phase of CSR remains unknown. Here, we provide evidence that acetylated histone reader Brd4 is critical to the repair and recombination step of CSR. Brd4 was recruited to the AID-induced DNA break region, and depletion of Brd4 from the S region chromatin by knockdown or a chemical inhibitor JQ1 causes CSR impairment without affecting AID-induced DNA break generation. Such inhibition of Brd4 suppressed the accumulation of 53BP1 and UNG at the cleaved S regions, perturbed switch donor-switch acceptor microhomology length and reduced Igh/c-myc translocation. We conclude that Brd4 serves as a histone-reader platform required for the recruitment of CSR repair components. Brd4 were depleted from the chromatin by either siRNA treatment or JQ1 (40nM) addition in CH12F3-2A cells in the presence of CIT stimulation. RNA from each samples were extracted and relative difference in transcript level were compared with control RNAi- and DMSO-treated, CIT-stimulated samples.

2014-06-20 | E-GEOD-52239 | biostudies-arrayexpress

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-Seq II]

Project description:The histone acetylation reader ENL is identifed as a key factor controlling super-enhancer-driven transcription. We thus perturbed BRD4, a well-known super-enhancer regulator, protein expression with a well-validated BRD4 PROTAC (proteolysis targeting chimeric) compound dBET1 and examined whether BRD4 was required for proper function of ENL in regulation gene transcription.

2024-01-18 | GSE249552 | GEO

MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.

Project description:MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function. BE(2)-C neuroblastoma cells were treated with the pan-HDACi HC-toxin (20 nM) or solvent control (methanol) for 24 h in three replicates, respectively.Total RNA was isolated using miRNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. RNA was eluted in water. The quality of total RNA was checked by gel analysis using the total RNA Nanochip assay on an Agilent 2100 Bioanalyzer.

2013-05-01 | E-GEOD-44538 | biostudies-arrayexpress

HDAC inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability

Project description:Histone deacetylases (HDACs) are critical in the control of gene expression and dysregulation of their activity has been implicated in a broad range of diseases including cancer, cardiovascular and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. While it has also been suggested that HDACi with increased isozyme-selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi SAHA and TSA. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histoneacetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that the evaluation of different classes of HDACi compounds using recombinant HDACs or histone acetylation is insufficient to predict their functional impact on cell activity. Control, SAHA 6hr, SAHA 24hr, SAHA 24hr (pulsed), C1 6hr, C1, 24hr, C1 24hr (pulsed)

2013-08-01 | E-GEOD-49158 | biostudies-arrayexpress

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data