METTL7B is an essential epigenetic regulator of lineage specification in glioblastoma [scRNAseq]

Glioblastomas are the most common malignant brain tumours in adults; they are highly aggressive, heterogeneous and plastic. We have identified METTL7B as an essential regulator of lineage specification in glioblastoma, with impact on both tumour size and invasiveness in in vivo models. Single cell transcriptomic analysis of these tumours and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B identified a regulatory role for the gene in the neural stem cells to astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via DNA methylation and post-translational modifications of histone marks. Overall design: 1) scRNAseq of GIC xenografts, with scrambled or anti-METTL7B shRNA 2) scRNAseq of control (PK/PK-Cas9) COs vs METTL7B-OE COs

胶质母细胞瘤（Glioblastomas）是成人最常见的恶性脑肿瘤，具有高侵袭性、异质性与可塑性。本研究鉴定出METTL7B是胶质母细胞瘤细胞谱系特化的关键调控因子，其在体内模型中可同时影响肿瘤体积与侵袭能力。针对该类肿瘤以及过表达METTL7B的扩展潜能干细胞（expanded potential stem cells）来源的脑类器官（cerebral organoids, COs）开展单细胞转录组分析（single cell transcriptomic analysis）后发现，该基因在神经干细胞向星形胶质细胞的分化轨迹中发挥调控作用。机制层面，METTL7B通过DNA甲基化与组蛋白标记的翻译后修饰，下调包括SALL2在内的关键神经分化调控因子的表达。实验设计概况：1) 转染阴性对照短发卡RNA或靶向METTL7B短发卡RNA的胶质瘤起始细胞（glioblastoma-initiating cells, GIC）异种移植瘤的单细胞RNA测序（single-cell RNA sequencing, scRNAseq）；2) 对照组（PK/PK-Cas9）脑类器官与METTL7B过表达脑类器官（METTL7B-OE COs）的单细胞RNA测序。