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KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236170 | GEO | 2024/01/17

REPOSITORIES: GEO

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KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [ChIP-seq]

Project description:A series of Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) experiments were conducted to investigate the effect and mechanism of KDM5C on the recruitment of BRD4 to chromatin, and the effect of this process on histone modification and gene expression. We then performed ChIP-seq for BRD4, KDM5C, H3K27ac, H3K4me3, and H3K4me1 in HeLa and its derivatives cell lines.

2024-01-17 | GSE236169 | GEO

KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [RNA-seq]

Project description:To investigate the effect of the KDM5C depletion on transcription, we established HeLa cell lines in which KDM5C has been knocked off. To explore the effect of synergistic lethal action of KDM5C PROTAC drug and BETi on transcription, we treated HeLa cells with JQ1, or compound 3b, or in combination.

2024-01-17 | GSE236168 | GEO

KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity

Project description:KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity

| PRJNA989159 | ENA

KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [RNA-seq]

Project description:KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [RNA-seq]

| PRJNA989162 | ENA

KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [ChIP-seq]

Project description:KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [ChIP-seq]

| PRJNA989164 | ENA

Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer.

Project description:Bromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer.

| S-EPMC9588789 | biostudies-literature

BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice.

Project description:Precise regulation of transcription is crucial for the cellular mechanisms underlying memory formation. However, the link between neuronal stimulation and the proteins that directly interact with histone modifications to activate transcription in neurons remains unclear. Brd4 is a member of the bromodomain and extra-terminal domain (BET) protein family, which binds acetylated histones and is a critical regulator of transcription in many cell types, including transcription in response to external cues. Small molecule BET inhibitors are in clinical trials, yet almost nothing is known about Brd4 function in the brain. Here we show that Brd4 mediates the transcriptional regulation underlying learning and memory. The loss of Brd4 function affects critical synaptic proteins, which results in memory deficits in mice but also decreases seizure susceptibility. Thus Brd4 provides a critical link between neuronal activation and the transcriptional responses that occur during memory formation.

| S-EPMC4752120 | biostudies-literature

DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4.

Project description:The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.

| S-EPMC6086352 | biostudies-literature

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.

Project description:Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

| S-EPMC5882533 | biostudies-literature

Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA.

Project description:BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3' UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.

| S-EPMC4972677 | biostudies-literature

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