TY - JOUR TI - H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers AU - Fang, Dong AU - Gan, Haiyun AU - Cheng, Liang AU - Lee, Jeong-Heon AU - Zhou, Hui AU - Sarkaria, Jann N AU - Daniels, David J AU - Zhang, Zhiguo A2 - Workman, Jerry L VL - 7 PY - 2018 DA - 2018/06/22 SP - e36696 C1 - eLife 2018;7:e36696 DO - 10.7554/eLife.36696 UR - https://doi.org/10.7554/eLife.36696 AB - 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. KW - diffuse intrinsic pontine glioma KW - H3.3K27M KW - PRC2 KW - H3K27me3 KW - tumor suppressor gene KW - WT1 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -