Histone variant H2AFV equips glioblastoma stem cells with transcriptional potency and efficient DNA damage response [ATAC-seq]

Tumors are composed of cellular subpopulations with varying degree of proliferative and tumorigenic potential. Here, we identify inter- and intra-tumor heterogeneous expression of histone variant H2AFV in numerous cancer types, with high H2AFV expression correlating with cancer stem cells, poorly differentiated tumors and inferior patient survival. Depletion of H2AFV impairs proliferation, invasiveness, tumorigenicity and tumor initiating cell frequency of glioblastoma. Mechanistically, H2AFV regulates chromatin accessibility of both active and repressive complexes at the promoters and enhancers of genes: the former activates genes involved in cell proliferation/self-renewal and invasiveness while the latter suppresses cellular differentiation in cancer stem cells. Our studies uncover H2AFV as an important epigenetic determinant in cancer stem cell fate and a significant contributor of intratumor heterogeneity. ATAC-seq from glioblastoma stem cell specimens (TS-543) following treatment either with non-targeting or targeting shRNA.

肿瘤由具有不同增殖与致瘤潜能的细胞亚群构成。本研究在多种癌症类型中鉴定出组蛋白变体H2AFV存在肿瘤间与肿瘤内的异质性表达，且H2AFV高表达与癌症干细胞、低分化肿瘤及患者生存期缩短显著相关。敲低H2AFV会削弱胶质母细胞瘤的增殖能力、侵袭性、致瘤性与肿瘤起始细胞频率。机制层面而言，H2AFV可调控基因启动子与增强子区域内激活型与抑制型复合物的染色质可及性：前者激活参与细胞增殖/自我更新及侵袭过程的基因，后者抑制癌症干细胞的细胞分化。本研究揭示H2AFV是调控癌症干细胞命运的重要表观遗传决定因子，同时也是肿瘤内异质性的关键贡献因素。本数据集为经非靶向或靶向短发夹RNA（short hairpin RNA）处理的胶质母细胞瘤干细胞样本（TS-543）的ATAC-seq测序数据。