小柯机器人

加拿大犹太总医院Claudia L. Kleinman和加拿大麦吉尔大学Nada Jabado共同合作，近期取得重要工作进展。他们研究发现典型和非典型H3变体的K27M突变出现在大脑中线胶质瘤不同少突胶质细胞谱系中。相关研究成果2022年12月5日在线发表于《自然—遗传学》杂志上。

据介绍，典型（H3.1/H3.2）和非典型（H3.3）组蛋白3 K27M突变胶质瘤具有独特的时空分布、伴侣改变和分子图谱。原生细胞对这些差异的贡献一直以来都很难与突变诱发的致癌性重编程脱钩。

通过对116个肿瘤进行综合分析（包括单细胞转录组和染色质可及性、3D染色质结构和表观基因组图谱），研究人员发现，K27M突变胶质瘤在发育基因上忠实地保持染色质构型，与解剖学上不同的少突胶质细胞前体细胞（OPC）一致。H3.3K27M丘脑胶质瘤与prosomere 2源性谱系有关。反过来，H3.1K27M ACVR1突变脑桥胶质瘤反映早期腹侧NKX6-1⁺/SHH依赖性脑干OPC，而H3.3K27M胶质瘤通常类似于背侧PAX3⁺/BMP依赖性祖细胞。

研究数据表明，H3.1K27M突变SHH依赖性腹侧OPC存在特定环境的脆弱性，其依赖ACVR1突变的获得来驱动肿瘤发生所需的异常BMP信号。K27M突变的统一作用是在PRC2着落位点限制H3K27me3，而其他表观遗传变化主要取决于起源细胞染色质状态和循环速率。

附：英文原文

Title: K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Author: Jessa, Selin, Mohammadnia, Abdulshakour, Harutyunyan, Ashot S., Hulswit, Maud, Varadharajan, Srinidhi, Lakkis, Hussein, Kabir, Nisha, Bashardanesh, Zahedeh, Hbert, Steven, Faury, Damien, Vladoiu, Maria C., Worme, Samantha, Coutelier, Marie, Krug, Brian, Faria Andrade, Augusto, Pathania, Manav, Bajic, Andrea, Weil, Alexander G., Ellezam, Benjamin, Atkinson, Jeffrey, Dudley, Roy W. R., Farmer, Jean-Pierre, Perreault, Sebastien, Garcia, Benjamin A., Larouche, Valrie, Blanchette, Mathieu, Garzia, Livia, Bhaduri, Aparna, Ligon, Keith L., Bandopadhayay, Pratiti, Taylor, Michael D., Mack, Stephen C., Jabado, Nada, Kleinman, Claudia L.

Issue&Volume: 2022-12-05

Abstract: Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate.

DOI: 10.1038/s41588-022-01205-w

Source: https://www.nature.com/articles/s41588-022-01205-w

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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