H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers

• Published in: eLife Vol. 7
• Main Authors: Fang, Dong, Gan, Haiyun, Cheng, Liang, Lee, Jeong-Heon, Zhou, Hui, Sarkaria, Jann N, Daniels, David J, Zhang, Zhiguo
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 22.06.2018; eLife Sciences Publications, Ltd
• Subjects: Brain cancer; Brain Stem Neoplasms - genetics; Brain Stem Neoplasms - metabolism; Brain Stem Neoplasms - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; Cell Proliferation; Cellular Reprogramming; Chromosomes and Gene Expression; diffuse intrinsic pontine glioma; Enhancer Elements, Genetic; Enhancers; Epigenetics; Epigenomics; Gene Expression Regulation, Neoplastic; Genes; Genomes; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; H3.3K27M; H3K27me3; Histone H3; Histones - genetics; Histones - metabolism; Humans; Insects; Medical research; Methylation; Mutation; Neuroglia - metabolism; Neuroglia - pathology; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; PRC2; Promoter Regions, Genetic; Proteins; tumor suppressor gene; Tumor suppressor genes; Tumorigenesis; WT1; WT1 protein; WT1 Proteins - genetics; WT1 Proteins - metabolism; United States > US; mouse; PRC2; WT1; chromosomes; human; diffuse intrinsic pontine glioma; gene expression; tumor suppressor gene; H3.3K27M; H3K27me3
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.36696

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.