表观遗传学
癌症研究
生物
胶质瘤
干细胞
周细胞
细胞生物学
染色质
转录组
表型
组蛋白
内皮干细胞
基因表达
基因
遗传学
体外
作者
Sree Deepthi Muthukrishnan,Riki Kawaguchi,Pooja Nair,Rachna Prasad,Yue Qin,Mai Johnson,Qing Wang,Nathan Vanderveer-Harris,Amy Trinh Pham,Alvaro G. Alvarado,Michael C. Condro,Fuying Gao,Raymond Gau,Maria G. Castro,Pedro R. Lowenstein,Arjun Deb,Jason D Hinman,Frank Pajonk,Terry C. Burns,Steven A. Goldman,Daniel H. Geschwind,Harley I. Kornblum
标识
DOI:10.1038/s41467-022-33943-0
摘要
Abstract Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.
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