Bromodomain protein 9 (BRD9) regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA735132 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR14730209_1.fastq.gz | Fastqsanger.gz | |||
| SRR14730209_2.fastq.gz | Fastqsanger.gz | |||
| SRR14730210_1.fastq.gz | Fastqsanger.gz | |||
| SRR14730210_2.fastq.gz | Fastqsanger.gz |
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Project description:Macrophages induce a number of inflammatory response genes in response to stimulation with microbial ligands. In response to endotoxin Lipid A, lineage-defining and stimulation-responsive transcription factors cooperate to induce a gene activation cascade of primary followed by secondary response genes. Epigenetic state is an important regulator of the kinetics, specificity, and mechanism of gene activation of these two classes. In particular, the SWI/SNF chromatin remodeling complex is required for the activation secondary response genes, but not primary response genes, which generally exhibit open chromatin. Here we show that a recently discovered variant of the SWI/SNF complex, the non-canonical BAF complex (ncBAF), regulates secondary response genes in the interferon (IFN) response pathway. Inhibition of bromodomain-containing protein 9 (BRD9), a subunit of the ncBAF complex, with BRD9 bromodomain inhibitors (BRD9i) or a degrader (dBRD9), led to reduction in a number of interferon-stimulated genes (ISGs) following stimulation with endotoxin lipid A. BRD9-dependent genes overlapped highly with a subset of genes differentially regulated by BET protein inhibition with JQ1 following endotoxin stimulation. We find that the BET protein BRD4 is co-bound with BRD9 in unstimulated macrophages and co-recruited upon stimulation to ISG promoters along with STAT1, STAT2, and IRF9, components of the ISGF3 complex activated downstream of IFNAR stimulation. In the presence of BRD9i or dBRD9, STAT1, STAT2, and IRF9 binding is reduced, in some cases with reduced binding of BRD4. These results demonstrate a specific role for BRD9 and the ncBAF complex in ISG activation and identify an activity for BRD9 inhibitors and degraders in dampening endotoxin- and IFN-dependent gene expression.
2021-11-26 | GSE176146 | GEO
Project description:During heat stress cyto-protective genes including heat shock proteins are transcriptionally up-regulated and post-transcriptional splicing is inhibited. In contrast, co-transcriptional mRNA-splicing is maintained. These factors closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response. Furthermore, there is evidence for BRD4's role in splicing regulation; Using RNA-Seq analyses we indeed found a significant increase in splicing inhibition, in particular intron retentions, during heat treatment in BRD4-deficient cells, but not under normal conditions. Subsequent experiments revealed that heat stress leads to the recruitment of BRD4 to nuclear stress bodies, to the interaction with the heat shock factor 1 (HSF1) and to the transcriptional up-regulation of non-coding Sat III RNA transcripts. These findings implicate BRD4 as a central regulator of splicing during heat stress. Since BRD4 is a potent target for anti-cancer therapies, our data linking BRD4 to the splicing machinery and the heat stress response - give additional insight into the mode of action of BRD4 inhibitors. WI38 cells have been treated by heatshock and anti BRD4 siRNA and combination.
2016-09-07 | E-GEOD-73471 | biostudies-arrayexpress
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
Project description:DNA damage activates a complex signaling network in cells that blocks cell cycle progression, recruits factors involved in DNA repair, and/or triggers programs that control senescence or programmed cell death. Alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, although the molecular details are unclear. We investigated the role of chromatin structure in the DNA damage response by monitoring multiple timedependent checkpoint signaling and response events with a high-content multiplex image-based RNAi screen of chromatin modifying and interacting genes. We discovered that Brd4, a double bromodomain-containing protein, functions as an endogenous inhibitor of DNA damage signaling by binding to acetylated histones at sites of open chromatin and altering chromatin accessibility. Loss of Brd4 or disruption of acetyl-lysine binding results in an increase in both the number and size of radiation-induced !H2AX nuclear foci while overexpression of a Brd4 splice isoform completely suppresses !H2AX formation, despite equivalent double strand break formation. Brd4 knock-down cells displayed altered chromatin structure, prolonged cell cycle checkpoint arrest and enhanced survival after irradiation, while overexpression of Brd4 isoform B results in enhanced radiationinduced lethality. Brd4 is the target of the t(15;19) chromosomal translocation in a rare form of cancer, NUT Midline Carcinoma. Acetyl lysine-bromodomain interactions of the Brd4-NUT fusion protein suppresses !H2AX foci in discrete nuclear compartments, rendering cells more radiosensitive, mimicking overexpression of Brd4 isoform B. NUT Midline Carcinoma is sensitive to radiotherapy, however tumor material from this rare cancer is scarce. We therefore investigated Brd4 expression in another human cancer commonly treated with radiotherapy, glioblastoma multiforme, and found that expression of Brd4 isoform B correlated specifically with treatment response to radiotherapy. These data implicate Brd4 as an endogenous insulator of DNA damage signaling through recognition of epigenetic modifications in chromatin and suggest that expression of the Brd4 in human cancer can modulate the clinical response to DNA-damaging cancer therapy. Two replicates each of U2OS cells expressing either Brd4 shRNA or a control shRNA
2013-07-14 | E-GEOD-30700 | biostudies-arrayexpress
Project description:During heat stress cyto-protective genes including heat shock proteins are transcriptionally up-regulated and post-transcriptional splicing is inhibited. In contrast, co-transcriptional mRNA-splicing is maintained. These factors closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response. Furthermore, there is evidence for BRD4's role in splicing regulation; Using RNA-Seq analyses we indeed found a significant increase in splicing inhibition, in particular intron retentions, during heat treatment in BRD4-deficient cells, but not under normal conditions. Subsequent experiments revealed that heat stress leads to the recruitment of BRD4 to nuclear stress bodies, to the interaction with the heat shock factor 1 (HSF1) and to the transcriptional up-regulation of non-coding Sat III RNA transcripts. These findings implicate BRD4 as a central regulator of splicing during heat stress. Since BRD4 is a potent target for anti-cancer therapies, our data linking BRD4 to the splicing machinery and the heat stress response - give additional insight into the mode of action of BRD4 inhibitors.
2016-09-07 | GSE73471 | GEO
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.
2012-11-14 | GSE33281 | GEO
Project description:The mammalian BRG1-associated factors (BAF) complex is a multi-subunit chromatin remodeling complex that is an important component of the embryonic stem cell (ESC) transcriptional regulatory network. However, the role of individual subunits in BAF complex targeting and function needs to be elucidated. Here, we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1; also known as BICRA) or its paralog GLTSCR1-like (also known as BICRAL) define a smaller, non-canonical BAF complex (GBAF for GLTSCR1/1L-containing BAF complex) in mouse ESCs that is distinct from the canonical embryonic stem cell BAF (esBAF) and the polybromo-associated BAF (PBAF) complexes. GBAF lacks several esBAF subunits, including BAF47, BAF57 and ARID1A. We demonstrate that GBAF and esBAF complexes are targeted to different features of the genome and are co-bound with different sets of pluripotency transcription factors. Specifically, GBAF complexes co-localize with key regulators of naïve pluripotency, KLF4 and Sp5, on the genome. Consistent with this, we provide evidence that GBAF's specific function is to regulate the transcription of genes involved in the maintenance of naïve pluripotency, including Nanog and Prdm14. Additionally, we show that BRD9 is displaced from chromatin by the selective BRD9 bromodomain inhibitor, I-BRD9, and that this leads to changes in target gene expression. The function of the GBAF complex in ESCs is highly correlated with the function of BRD4, consistent with an association between GBAF complexes and BRD4. We find that GBAF complexes are directly recruited to chromatin by BRD4 in a bromodomain-dependent fashion and we identify a set of I-BRD9- and JQ1-sensitive BRD9 binding sites that determine the functional similarity between these epigenetic regulators. Together, our results demonstrate functionally specific roles for BAF complex assemblies in maintaining the transcriptional network of pluripotency, highlighting the biological importance of complex heterogeneity.
2018-10-19 | GSE111264 | GEO
Project description:DNA damage activates a complex signaling network in cells that blocks cell cycle progression, recruits factors involved in DNA repair, and/or triggers programs that control senescence or programmed cell death. Alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, although the molecular details are unclear. We investigated the role of chromatin structure in the DNA damage response by monitoring multiple timedependent checkpoint signaling and response events with a high-content multiplex image-based RNAi screen of chromatin modifying and interacting genes. We discovered that Brd4, a double bromodomain-containing protein, functions as an endogenous inhibitor of DNA damage signaling by binding to acetylated histones at sites of open chromatin and altering chromatin accessibility. Loss of Brd4 or disruption of acetyl-lysine binding results in an increase in both the number and size of radiation-induced !H2AX nuclear foci while overexpression of a Brd4 splice isoform completely suppresses !H2AX formation, despite equivalent double strand break formation. Brd4 knock-down cells displayed altered chromatin structure, prolonged cell cycle checkpoint arrest and enhanced survival after irradiation, while overexpression of Brd4 isoform B results in enhanced radiationinduced lethality. Brd4 is the target of the t(15;19) chromosomal translocation in a rare form of cancer, NUT Midline Carcinoma. Acetyl lysine-bromodomain interactions of the Brd4-NUT fusion protein suppresses !H2AX foci in discrete nuclear compartments, rendering cells more radiosensitive, mimicking overexpression of Brd4 isoform B. NUT Midline Carcinoma is sensitive to radiotherapy, however tumor material from this rare cancer is scarce. We therefore investigated Brd4 expression in another human cancer commonly treated with radiotherapy, glioblastoma multiforme, and found that expression of Brd4 isoform B correlated specifically with treatment response to radiotherapy. These data implicate Brd4 as an endogenous insulator of DNA damage signaling through recognition of epigenetic modifications in chromatin and suggest that expression of the Brd4 in human cancer can modulate the clinical response to DNA-damaging cancer therapy.
2013-07-14 | GSE30700 | GEO
Project description:The mammalian BRG1-associated factors (BAF) complex is a multi-subunit chromatin remodeling complex that is an important component of the embryonic stem cell (ESC) transcriptional regulatory network. However, the role of individual subunits in BAF complex targeting and function needs to be elucidated. Here, we find that the Bromodomain containing protein 9 (BRD9) defines a smaller, non-canonical BAF complex in mouse ESCs that is distinct from the canonical embryonic stem cell BAF (esBAF) and the polybromo-associated BAF (PBAF) complexes. This BRD9-containing BAF complex, or BBAF complex, uniquely incorporates the BRD4-interacting chromatin remodeling associated protein-like (BICRAL) or its paralog BICRA and lacks several esBAF subunits including BAF47, ARID1A and BAF57. We demonstrate that BBAF and esBAF complexes are targeted to different features of the genome and are co-bound with different sets of pluripotency transcription factors. Specifically, BBAF complexes co-localize with key regulators of naïve pluripotency, KLF4 and Sp5, on the genome. Consistent with this, we provide evidence that BBAF’s specific function is to regulate the transcription of genes involved in the maintenance of naïve pluripotency, including Nanog and Prdm14. Additionally, we show that BRD9 is displaced from chromatin by the selective BRD9 bromodomain inhibitor, I-BRD9, and that this leads to changes in target gene expression. Together, our results provide evidence for the identification of a new BAF complex, and demonstrate functionally specific roles for BAF complex assemblies in maintaining the transcriptional network of pluripotency.
2018-10-18 | PXD010670 | Pride
Project description:Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection
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