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BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [ChIP-seq]

ABSTRACT: BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [ChIP-seq]

PROVIDER: PRJNA430819 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6502740.fastq.gz	Fastqsanger.gz
	SRR6502750.fastq.gz	Fastqsanger.gz
	SRR6502760.fastq.gz	Fastqsanger.gz
	SRR6502770.fastq.gz	Fastqsanger.gz
	SRR6502780.fastq.gz	Fastqsanger.gz

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Similar Datasets

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [expression profiling]

2018-04-17 | GSE109587 | GEO

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [ChIP-seq]

2018-04-17 | GSE109411 | GEO

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor

Project description:BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor

| PRJNA431438 | ENA

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [expression profiling]

Project description:BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor [expression profiling]

| PRJNA431429 | ENA

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

Hematopoietic transcription factors and p300/CBP shape the effects of BET bromodomain inhibition in leukemia [ChIP-Seq]

Project description:The bromodomain and extraterminal (BET) protein Brd4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that Brd4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) Pu.1, Fli1, Erg, C/EBPα, C/EBPβ, and Myb at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate Brd4 recruitment to their occupied sites to promote transcriptional activation. Moreover, chemical inhibition of BET bromodomains is found to suppress the functional output each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and Brd4, which supports leukemia maintenance and is suppressed by BET bromodomain inhibition. ChIP-Seq for regulatory factors of Brd4 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2015-05-01 | E-GEOD-66122 | biostudies-arrayexpress

Hematopoietic transcription factors and p300/CBP shape the effects of BET bromodomain inhibition in leukemia [RNA-Seq]

Project description:The bromodomain and extraterminal (BET) protein Brd4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that Brd4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) Pu.1, Fli1, Erg, C/EBPα, C/EBPβ, and Myb at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate Brd4 recruitment to their occupied sites to promote transcriptional activation. Moreover, chemical inhibition of BET bromodomains is found to suppress the functional output each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and Brd4, which supports leukemia maintenance and is suppressed by BET bromodomain inhibition. PolyA selected RNA-Seq for drug treated or shRNA-expressing MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2015-05-01 | E-GEOD-66068 | biostudies-arrayexpress

BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-04-17 | GSE109593 | GEO

Selectivity of 2J2V for BET proteins in A549 cells

Project description:Data independent acquisition (DIA) mass spectrometry was used to study the selectivity of 2J2V for BET proteins from A549 cells. BET proteins, BRD2, BRD3 and BRD4 were observed to be degraded the most by 2J2V in comparison to MZ1 or DMSO.

2024-10-08 | PXD049407 | Pride

: Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

Project description:BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4-dependent transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interact with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 enrichment at the hyper-acetylated chromatin regions. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 function and highlight targeting PRMT2/4 for better anti-tumor effect of BET inhibitors and DNA damaging agents.

2023-03-11 | PXD034650 | Pride

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