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利用Strand-seq对单细胞中的结构变体进行功能分析
作者:小柯机器人 发布时间:2022/11/27 21:17:06

德国欧洲分子生物学实验室Jan O. Korbel和Ashley D. Sanders共同合作,近期取得重要工作进展。他们研究利用Strand-seq对单细胞中的结构变体进行功能分析。该项研究成果2022年11月24日在线发表于《自然—生物技术》杂志上。

研究人员开发出一种计算方法,scNOVA,该方法使用Strand-seq,通过使用核小体占有率推断基因表达作为读数,在单个细胞中进行SV发现和分子表型的单倍型感知整合。在白血病和细胞系中的应用确定了复制平衡重排对基因失调的局部影响,以及SV对亚克隆中异常信号通路的影响。研究人员在一名慢性淋巴细胞白血病患者中发现了具有Wnt信号失调的SV亚克隆。他们进一步发现了T细胞急性淋巴细胞白血病中亚克隆染色体碎裂的后果,揭示了c-Myb活化,原始细胞状态的富集。研究人员还发现,在培养细胞中使用Notch抑制剂能成功靶向亚克隆。通过直接将SV与其功能效应联系起来,scNOVA能够实现对异质细胞群体中的结构变化进行系统的单细胞多组学研究。

据介绍,体细胞结构变异(SV)在癌症中广泛存在,但由于缺乏直接表征其功能的方法,SV对疾病演化的影响尚未得到充分研究。

附:英文原文

Title: Functional analysis of structural variants in single cells using Strand-seq

Author: Jeong, Hyobin, Grimes, Karen, Rauwolf, Kerstin K., Bruch, Peter-Martin, Rausch, Tobias, Hasenfeld, Patrick, Benito, Eva, Roider, Tobias, Sabarinathan, Radhakrishnan, Porubsky, David, Herbst, Sophie A., Erarslan-Uysal, Bra, Jann, Johann-Christoph, Marschall, Tobias, Nowak, Daniel, Bourquin, Jean-Pierre, Kulozik, Andreas E., Dietrich, Sascha, Bornhauser, Beat, Sanders, Ashley D., Korbel, Jan O.

Issue&Volume: 2022-11-24

Abstract: Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration of SV discovery and molecular phenotyping in single cells by using nucleosome occupancy to infer gene expression as a readout. Application to leukemias and cell lines identifies local effects of copy-balanced rearrangements on gene deregulation, and consequences of SVs on aberrant signaling pathways in subclones. We discovered distinct SV subclones with dysregulated Wnt signaling in a chronic lymphocytic leukemia patient. We further uncovered the consequences of subclonal chromothripsis in T cell acute lymphoblastic leukemia, which revealed c-Myb activation, enrichment of a primitive cell state and informed successful targeting of the subclone in cell culture, using a Notch inhibitor. By directly linking SVs to their functional effects, scNOVA enables systematic single-cell multiomic studies of structural variation in heterogeneous cell populations.

DOI: 10.1038/s41587-022-01551-4

Source: https://www.nature.com/articles/s41587-022-01551-4

期刊信息

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:31.864
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex