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.
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.
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.
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.
Project description:To assess whether BH4Ds are more or less sensitive than sharp H3K4me3 peaks to perturbation of H3K4me3 levels, we performed H3K4me3 ChIP-seq experiments from Jurkat cells treated with DMSO or with either 2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), a specific inhibitor of JARID1 family of H3K4me3 demethylases, also known as KDM5, or OICR-9429, an inhibitor of the MLL-WDR5, previously shown to decrease cellular levels of H3K4me3.
Project description:Bone marrow-derived multipotent stromal cells (BM-MSCs) exhibit therapuetically valuable properties, including the capacity to differentiate into skeletal tissues and modulate immune system activity. These properties depend on proper regulation of dynamic gene expression in response to environmental and developmental stimuli. This study used chromatin immunoprecipitation (ChIP) coupled with human promoter tiling microarray analysis (ChIP-on-chip) to profile histones H3K4me3 and H3K27me3 at promoters genome-wide. The goal of the study was to identify gene promoters marked by H3K27me3 and H3K4me3 in BM-MSCs. ChIP-on-chip performed with antibodies to H3K4me3 and H3K27me3 on BM-MSCs from 3 different donors (labeled 1632, 167696, and 8F3560) and with technical replicates.