Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants.
Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants.
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DOI：
10.1016/j.stem.2021.01.016
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发表时间：
2021-05-06
期刊：
影响因子：
23.9
通讯作者：
Pollard SM
中科院分区：
文献类型：
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作者：
Bressan RB;Southgate B;Ferguson KM;Blin C;Grant V;Alfazema N;Wills JC;Marques-Torrejon MA;Morrison GM;Ashmore J;Robertson F;Williams CAC;Bradley L;von Kriegsheim A;Anderson RA;Tomlinson SR;Pollard SM
组蛋白 H3.3 内的点突变在被称为小儿高级别神经胶质瘤 (pHGG) 的侵袭性儿童脑肿瘤中很常见。有趣的是，不同的解剖区域出现不同的突变：前脑内的 H3.3-G34R 和后脑内的 H3.3-K27M 优先。这种截然不同的病因学的原因尚不清楚。通过从不同的大脑区域设计人类胎儿神经干细胞培养物，我们在此证明细胞固有的区域身份为每个突变体提供了不同的反应性，这反映了 pHGG 的起源。重点关注 H3.3-G34R，我们发现癌组蛋白支持前脑细胞增殖，同时诱导后脑细胞抑制反应。从机制上讲，H3.3-G34R 不会造成广泛的转录或表观遗传变化，而是会损害 ZMYND11（一种高表达基因的转录抑制因子）的募集。因此，我们提出H3.3-G34R通过局部稳定关键祖基因的表达来促进肿瘤发生，从而将起始前脑细胞锁定到其预先存在的未成熟状态。 H3.3 突变体 pHGG 的人类细胞模型工程 区域同一性为突变体 H3.3 反应提供了能力，反映了 pHGG H3.3-G34R 增强了预先存在的前脑祖细胞转录回路 G34R 突变破坏了转录抑制因子 ZMYND11 与 H3.3 的结合，来自不同解剖位置的儿科高级神经胶质瘤具有不同的 H3.3 突变。 Bressan 等人使用人类胎儿神经干细胞模型。发现区域同一性是细胞对 K27M 和 G34R 突变体的不同致癌反应的内在能力的基础。他们表明 H3.3-G34R 通过破坏 ZMYND11 结合来增强预先存在的前脑相关转录回路。
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. Engineering of human cellular models of H3.3 mutant pHGGs Regional identity provides competence for mutant H3.3 responses that mirrors pHGG H3.3-G34R reinforces pre-existing forebrain progenitor transcriptional circuits G34R mutation disrupts binding of the transcriptional repressor ZMYND11 to H3.3 Pediatric high-grade gliomas from different anatomical locations harbor distinct H3.3 mutations. Using human fetal neural stem cell models, Bressan et al. found that regional identity underlies cell-intrinsic competence for distinct oncogenic responses to K27M and G34R mutants. They show H3.3-G34R reinforces pre-existing forebrain-affiliated transcriptional circuits by disrupting ZMYND11 binding.
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影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
3.7
作者：
Hennika T;Hu G;Olaciregui NG;Barton KL;Ehteda A;Chitranjan A;Chang C;Gifford AJ;Tsoli M;Ziegler DS;Carcaboso AM;Becher OJ
通讯作者：
Becher OJ
影响因子：
14.9
作者：
Harris, MA;Clark, J;White, R
通讯作者：
White, R
影响因子：
7.7
作者：
Dewari, Pooran Singh;Southgate, Benjamin;Pollard, Steven M.
通讯作者：
Pollard, Steven M.
影响因子：
9.8
作者：
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