英国爱丁堡大学Steven M. Pollard团队取得一项新突破。他们发现人神经干细胞的区域特性决定了对组蛋白H3.3突变体的致癌反应。相关论文于2021年2月24日在线发表在《细胞-干细胞》杂志上。

通过对不同脑区人胎儿神经干细胞的工程化培养，研究人员发现细胞内在区域的同一性为小儿高级神经胶质瘤（pHGGs）每个突变体的不同来源提供了不同的响应能力。通过对H3.3-G34R的研究，研究人员发现癌蛋白支持前脑细胞的增殖，同时在后脑中诱导细胞抑制反应。从机理上讲，H3.3-G34R不会导致广泛的转录或表观遗传变化，而是会损害ZMYND11的招募，ZMYND11是高表达基因的转录阻遏物。

因此，研究人员提出H3.3-G34R通过稳定关键祖细胞基因的表达来促进肿瘤发生，从而将前脑细胞锁定为它们先前存在的未成熟状态。

据悉，组蛋白H3.3的点突变在恶性小儿脑肿瘤中很常见，该肿瘤又被称为pHGGs。引人注意的是，在离散的解剖区域中会发现明显的突变，如前脑内的H3.3-G34R和后脑内的H3.3-K27M。但尚不清楚其病因相反的原因。

附：英文原文

Title: Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants

Author: Raul Bardini Bressan, Benjamin Southgate, Kirsty M. Ferguson, Carla Blin, Vivien Grant, Neza Alfazema, Jimi C. Wills, Maria Angeles Marques-Torrejon, Gillian M. Morrison, James Ashmore, Faye Robertson, Charles A.C. Williams, Leanne Bradley, Alex von Kriegsheim, Richard A. Anderson, Simon R. Tomlinson, Steven M. Pollard

Issue&Volume: 2021-02-24

Abstract: Point mutations within the histone H3.3 are frequent in aggressive childhood brain tumors known as pediatric high-grade gliomas (pHGGs). Intriguingly, distinct mutations arise in discrete anatomical regions: H3.3-G34R within the forebrain and H3.3-K27M preferentially within the hindbrain. The reasons for this contrasting etiology are unknown. By engineering human fetal neural stem cell cultures from distinct brain regions, we demonstrate here that cell-intrinsic regional identity provides differential responsiveness to each mutant that mirrors the origins of pHGGs. Focusing on H3.3-G34R, we find that the oncohistone supports proliferation of forebrain cells while inducing a cytostatic response in the hindbrain. Mechanistically, H3.3-G34R does not impose widespread transcriptional or epigenetic changes but instead impairs recruitment of ZMYND11, a transcriptional repressor of highly expressed genes. We therefore propose that H3.3-G34R promotes tumorigenesis by focally stabilizing the expression of key progenitor genes, thereby locking initiating forebrain cells into their pre-existing immature state.

DOI: 10.1016/j.stem.2021.01.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00016-3