小柯机器人

美国杰克逊基因医学实验室Roel G. W. Verhaak、Kevin C. Johnson等研究人员合作通过单细胞多模式胶质瘤分析确定细胞可塑性和环境应激反应的表观遗传调节因子。相关论文于2021年9月30日在线发表在《自然—遗传学》杂志上。

研究人员整合了11个成年IDH突变型或IDH野生型胶质瘤的914个单细胞DNA甲基化组、55284个单细胞转录组和大量多组学资料，用于划定瘤内异质性的来源。结果表明，局部DNA甲基化紊乱与细胞-细胞DNA甲基化差异有关，在更具侵略性的肿瘤中升高，与转录破坏有关，并在环境应激反应期间发生改变。胶质瘤细胞在体外缺氧和辐照压力下，局部DNA甲基化紊乱增加，细胞状态发生转变。

研究人员确定了遗传和表观遗传不稳定之间的正相关，这在大量纵向收集的DNA甲基化数据中得到了支持。DNA甲基化紊乱的增加与疾病的加速发展有关，反复选择的DNA甲基化变化富含环境压力反应途径。这项工作确定了一个表观遗传促进的适应性应激反应过程，并强调了表观遗传异质性在塑造治疗结果中的重要性。

据悉，胶质瘤的瘤内异质性使其能够适应具有挑战性的微环境，并促成了治疗的耐药。

附：英文原文

Title: Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response

Author: Johnson, Kevin C., Anderson, Kevin J., Courtois, Elise T., Gujar, Amit D., Barthel, Floris P., Varn, Frederick S., Luo, Diane, Seignon, Martine, Yi, Eunhee, Kim, Hoon, Estecio, Marcos R. H., Zhao, Dacheng, Tang, Ming, Navin, Nicholas E., Maurya, Rahul, Ngan, Chew Yee, Verburg, Niels, de Witt Hamer, Philip C., Bulsara, Ketan, Samuels, Michael L., Das, Sunit, Robson, Paul, Verhaak, Roel G. W.

Issue&Volume: 2021-09-30

Abstract: Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell–cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.

DOI: 10.1038/s41588-021-00926-8

Source: https://www.nature.com/articles/s41588-021-00926-8

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
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex