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Hematopoietic transcription factors and p300/CBP shape the effects of BET bromodomain inhibition in leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Jae Seok Roe

PROVIDER: E-GEOD-66123 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-03-01 | E-GEOD-74651 | biostudies-arrayexpress

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

BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells (RNA-Seq I)

Project description:Genome occupancy profiling by high throughput sequencing PolyA selected RNA-seq for shRNA-expressing MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2016-03-01 | E-GEOD-74650 | biostudies-arrayexpress

BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells (RNA-Seq II)

Project description:Genome occupancy profiling by high throughput sequencing PolyA selected RNA-seq for shRNA-expressing MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2016-03-01 | E-GEOD-78224 | biostudies-arrayexpress

NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler (ChIP-Seq)

Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. ChIP-Seq for regulatory factors of BRD4, NSD3, CHD8 and histone modification H3K36me2 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2015-12-17 | E-GEOD-71183 | biostudies-arrayexpress

NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-17 | E-GEOD-71186 | biostudies-arrayexpress

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-02 | E-GEOD-52279 | biostudies-arrayexpress

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation (RNA-seq)

Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs To profile the basal transcription level, we performed NSR and PolyA+ (illumine TruSeq) in a murine AML RN2 cell lines. To define the rapid downregulated genes in response to JQ1, BET bromodomian inhibitor, in RN2 cell, we performed RNA-seq in RN2 exposing to 250nM JQ1 for 48h time course.

2013-12-02 | E-GEOD-52623 | biostudies-arrayexpress

BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells (ChIP-Seq I)

Project description:Genome occupancy profiling by high throughput sequencing ChIP-seq of Brd4 and Mediator with or without JQ1 treatment in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2016-03-01 | E-GEOD-74536 | biostudies-arrayexpress

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