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

ABSTRACT: 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. PolyA+ (illumine TruSeq)/not-so-random (NSR) primers selected RNA-Seq for shRNA/sgRNA-expressing MLL-AF9 transformed acute myeloid leukemia cells (RN2).

ORGANISM(S): Mus musculus

SUBMITTER: Christopher Vakoc

PROVIDER: E-GEOD-71185 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 (RNA-Seq)

2015-12-17 | GSE71185 | GEO

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

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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

An NSD3-targeting PROTAC suppresses the NSD3 and cMyc oncogenic nodes in cancer cells

Project description:Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in cancers, encodes a chromatin modulator and an attractive onco-target. However, agent that can effectively suppress the NSD3-mediated oncogenic actions is currently lacking. We report an NSD3-targeting proteolysis targeting chimera (PROTAC), termed MS9715, which achieves effective and specific depletion of NSD3 and interacting partners (including cMyc) in tumor cells. MS9715-induced NSD3 degradation relies on BI-9321, an antagonist module binding the PWWP1 domain of NSD3, and VHL, which is chemically conjugated to BI-9321 via a linker and VHL ligand module. Importantly, compared to BI-9321, a recently disclosed NSD3 antagonist, MS9715 is more potent in suppressing growth of the NSD3-dependent hematological cancer including models of MLL-rearranged acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM), and uniquely mediate simultaneous depletion of cellular NSD3 and cMyc. Transcriptome profiling further demonstrates effective actions of MS9715 but not BI-9321 in suppressing both NSD3- and cMyc-associated gene-expression programs, a phenomenon reminiscent of the CRISPR/cas9-mediated knockout (KO) of NSD3. Together, this study reports a first-in-class NSD3 PROTAC/degrader suitable for co-suppressing NSD3- and cMyc-related oncogenic nodes in cancer cells, suggesting a novel therapeutic strategy.

2021-08-27 | PXD021901 | Pride

An NSD3-targeting PROTAC (Proteolysis Targeting Chimeric) suppresses the NSD3 and cMyc oncogenic nodes in cancer cells

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2021-08-31 | GSE158296 | GEO

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

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 In order to understanding the transcription regulation network downstream of Brg1 in murine AML, we performed microarray in murine MLL-AF9/NrasG12D cell line under the condition that Brg1 was suppressed by three independent shRNAs for 96h.

2013-12-02 | E-GEOD-52231 | biostudies-arrayexpress

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

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

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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 Enhancer usually regulates its targets through physical contact/interaction. In order to study chromosome conformation of Myc locus and potential distal enhancer E1-E5 region in murine AML cells, we utilize the high resolution 4C-seq and analysis pipeline to search cis elements that physical interact with Myc and E1-E5 region through setting up two individual viewpoints in these two regions.

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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)

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