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研究揭示胶质瘤转录细胞状态的表观遗传编码、遗传力和可塑性
2021-10-09 14:25

美国纽约基因组研究所Dan A. Landau、哈佛医学院Mario L. Suvà等研究人员合作揭示胶质瘤转录细胞状态的表观遗传编码、遗传力和可塑性。相关论文于2021年9月30日在线发表在《自然—遗传学》杂志上。

研究人员表示,单细胞RNA测序揭示了癌症中广泛的转录细胞状态的多样性,通常独立于遗传异质性观察,因此提出了恶性细胞状态如何通过表观遗传学编码的核心问题。

为了解决这个问题,研究人员进行了多组学单细胞分析,整合了弥漫性胶质瘤的DNA甲基化、转录组和同一细胞内的基因型,这些肿瘤的特点是明确的转录细胞状态多样性。通过直接比较不同细胞状态的表观遗传图谱,研究人员揭示了再现神经发育轨迹的状态转换的关键开关,并强调了胶质瘤发病的表观遗传机制失调。研究人员进一步开发了一个定量框架,并基于人类样本的高分辨率谱系树直接测量了细胞状态的遗传性和过渡动态。

研究人员证明了恶性细胞状态的遗传力,而且在IDH突变型胶质瘤与IDH野生型胶质母细胞瘤中,层次性和可塑性的细胞状态架构分别存在关键差异。这项工作提供了一个框架,将转录性癌症细胞状态锚定在其表观遗传编码、继承和过渡动态中。

附:英文原文

Title: Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states

Author: Chaligne, Ronan, Gaiti, Federico, Silverbush, Dana, Schiffman, Joshua S., Weisman, Hannah R., Kluegel, Lloyd, Gritsch, Simon, Deochand, Sunil D., Gonzalez Castro, L. Nicolas, Richman, Alyssa R., Klughammer, Johanna, Biancalani, Tommaso, Muus, Christoph, Sheridan, Caroline, Alonso, Alicia, Izzo, Franco, Park, Jane, Rozenblatt-Rosen, Orit, Regev, Aviv, Suv, Mario L., Landau, Dan A.

Issue&Volume: 2021-09-30

Abstract: Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling—integrating DNA methylation, transcriptome and genotype within the same cells—of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.

DOI: 10.1038/s41588-021-00927-7

Source: https://www.nature.com/articles/s41588-021-00927-7

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


本期文章:《自然—遗传学》:Online/在线发表

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