爱尔兰都柏林圣三一大学Adrian P. Bracken等研究人员合作发现，PRC2和增强子功能的同时破坏是人类后脑神经干细胞中组蛋白H3.3-K27M致癌活性的基础。这一研究成果于2021年7月22日在线发表在国际学术期刊《自然—遗传学》上。

研究人员使用人类后脑神经干细胞来模拟了p.Lys27Met替换（H3-K27M）在相关发育背景下对表观基因组景观的影响。表位标记的组蛋白H3.3的全基因组图谱显示，野生型和K27M突变体都大量结合在预先存在的活跃增强子和启动子上，在较小程度上结合在多梳抑制复合物2（PRC2）结合区域。在活跃的增强子部位，H3.3-K27M导致局灶性的H3K27ac丢失，染色质可及性降低，以及附近神经发育基因的转录表达减少。此外，H3.3-K27M富集在PRC2靶基因的一个亚群中，导致PRC2和PRC1的结合增加和转录抑制增强，这可被PRC2抑制剂部分逆转。

这项工作表明，H3.3-K27M不是强加新的转录回路，而是通过破坏PRC2和增强子的功能，将起始细胞锁定在其预先存在的、不成熟的表观基因组状态，从而驱动肿瘤的发生。

据介绍，编码组蛋白H3蛋白的基因发生驱动性突变，导致H3-K27M在儿童中线脑瘤中频繁出现。然而，H3-K27M导致肿瘤发生的确切机制仍不清楚。

附：英文原文

Title: Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

Author: Gerard L. Brien, Raul Bardini Bressan, Craig Monger, Dire Gannon, Eimear Lagan, Anthony M. Doherty, Evan Healy, Hannah Neikes, Darren J. Fitzpatrick, Orla Deevy, Vivien Grant, Maria-Angeles Marqus-Torrejn, Neza Alfazema, Steven M. Pollard, Adrian P. Bracken

Issue&Volume: 2021-07-22

Abstract: Driver mutations in genes encoding histone H3 proteins resulting in p.Lys27Met substitutions (H3-K27M) are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context. Genome-wide mapping of epitope-tagged histone H3.3 revealed that both the wild type and the K27M mutant incorporate abundantly at pre-existing active enhancers and promoters, and to a lesser extent at Polycomb repressive complex 2 (PRC2)-bound regions. At active enhancers, H3.3-K27M leads to focal H3K27ac loss, decreased chromatin accessibility and reduced transcriptional expression of nearby neurodevelopmental genes. In addition, H3.3-K27M deposition at a subset of PRC2 target genes leads to increased PRC2 and PRC1 binding and augmented transcriptional repression that can be partially reversed by PRC2 inhibitors. Our work suggests that, rather than imposing de novo transcriptional circuits, H3.3-K27M drives tumorigenesis by locking initiating cells in their pre-existing, immature epigenomic state, via disruption of PRC2 and enhancer functions. The oncohistone H3.3-K27M decreases chromatin accessibility and H3K27ac at some active enhancers and downregulates nearby neurodevelopmental genes, while increasing transcriptional repression of a subset of PRC2-bound neurodevelopment genes.

DOI: 10.1038/s41588-021-00897-w

Source: https://www.nature.com/articles/s41588-021-00897-w