Identification of a novel role of MTF2 in the regulation of H3K27me3 by PRC2 (RNA-Seq)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE111145 | GEO | 2018/02/27
REPOSITORIES: GEO
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Project description:The project aimed at determining whether the Polycomb complex PRC2 has a unique composition in androgen independent prostate cancer cells and the project aimed at determining whether EZH2, the enzymatic subunit of PRC2, retains any functional role in the context of Malignant peripheral nerve sheath tumor (MPNST) where either EED or SUZ12, two essential subunits of PRC2 are inactivated.
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Project description:Polycomb Repressive Complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during hematopoiesis. We examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 sub-complex lacking EED. We provide evidence that EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin domains in the absence of H3K27me3, and positively regulate gene expression. Loss of EZH2 expression leads to global repositioning of EZH1 chromatin occupancy to EZH2 targets. Moreover, we demonstrate that an erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers during erythropoiesis. Thus, the lineage- and developmental stage-specific regulation of PRC2 expression and subunit composition leads to a switch from canonical silencing to non-canonical PRC2 functions during blood stem cell specification. Transcriptional profiling in primary human fetal liver proerythroblasts upon lentiviral shRNA-mediated knockdown of EZH1, EZH2, EED, or SUZ12 by RNA-seq analysis.
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Project description:Polycomb Repressive Complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during hematopoiesis. We examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 sub-complex lacking EED. We provide evidence that EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin domains in the absence of H3K27me3, and positively regulate gene expression. Loss of EZH2 expression leads to global repositioning of EZH1 chromatin occupancy to EZH2 targets. Moreover, we demonstrate that an erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers during erythropoiesis. Thus, the lineage- and developmental stage-specific regulation of PRC2 expression and subunit composition leads to a switch from canonical silencing to non-canonical PRC2 functions during blood stem cell specification. Analysis of genomic occupancy of EZH1, EZH2, EED, SUZ12, various histone marks and transcription factors in primary human fetal liver proerythroblasts by ChIP-seq. Sample GSM970262 was used as the input DNA sample.
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Project description:Polycomb repressive complex (PRC) 2, containing minimally EZH2, EED and Suz12, is the H3 lysine 27 methyltransferase playing pivotal roles in transcriptional regulation. EZH2 is the catalytic subunit, and H3K27me3 activates PRC2 through binding EED to propagate the repressive mark. Cofactor SAM-competitive (SAM-C) PRC2 inhibitors (PRC2is) have been discovered to treat lymphoma and rhabdoid tumors. Here we report the discovery of EED226, a potent and selective PRC2i directly binding to the H3K27me3 pocket of EED. Upon binding, EED226 induces conformational change in EED protein. Interestingly, it inhibits both the basal and the H3K27me3-stimulated PRC2 activities. Furthermore, EED226 selectively pulled down the endogenous PRC2 complex from human cell lysates, specifically modulates H3K27 methylation and target genes similarly as SAM-C PRC2 inhibitors, and effectively regresses human lymphoma xenograft tumor in mouse. More importantly, EED226 potently inhibits the SAM-C inhibitor-resistant PRC2 and synergizes with SAM-C PRC2i in cell proliferation blocking. Together, EED226 is an inhibitor of PRC2 with a novel mechanism and represent a potential complementary strategy for PRC2-targeted cancer therapy.
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Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that BMP-ACVR1 signaling pathway as a critical component for the anti-lymphoma efficacy of PRC2 inhibitor.
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Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that multiple senescence-associated secretory phenotype (SASP) genes, such as Gata4, Mmp2/10, Itga2 and Gbp1, are derepressed upon PRC2 inhibition and contribute to decreased Ki67+, ECM reorganization, inflammation and tumor regression even in Cdkn2a/p16 knockout tumor.
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Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that multiple senescence-associated secretory phenotype (SASP) genes, such as Gata4, Mmp2/10, Itga2 and Gbp1, are derepressed upon PRC2 inhibition and contribute to decreased Ki67+, ECM reorganization, inflammation and tumor regression even in Cdkn2a/p16 knockout tumor.
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Project description:This experiment sought to determine the chromatin structure and PRC2 occupancy at the promoters of all genes in mouse ESCs ChIP-seq for EZH2, SUZ12, and H3K27me3 were performed on WT E14 cells in 2 biological replicates each. In addition H3K27me3 ChIP-seq was also performed on a clone of E14 cells expressing a tagged version of EZH2, which for the purpose of this study was used as replicate #3.
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Project description:Polycomb Repressive Complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during hematopoiesis. We examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 sub-complex lacking EED. We provide evidence that EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin domains in the absence of H3K27me3, and positively regulate gene expression. Loss of EZH2 expression leads to global repositioning of EZH1 chromatin occupancy to EZH2 targets. Moreover, we demonstrate that an erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers during erythropoiesis. Thus, the lineage- and developmental stage-specific regulation of PRC2 expression and subunit composition leads to a switch from canonical silencing to non-canonical PRC2 functions during blood stem cell specification.
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