当前位置:科学网首页 > 小柯机器人 >详情
神经细胞中顺式调控染色质图谱成功绘制
来源:小柯机器人 发布时间:2019/8/5 21:00:29

加州大学旧金山分校Yin Shen研究小组的最新成果成功绘制神经细胞中顺式调控染色质图谱,将神经精神疾病遗传变异标记与标靶基因进行关联。该成果于2019年8月发表在国际顶尖杂志《自然—遗传学》上。

该课题组使用一种对染色质上相互作用的整合分析方法,包括:对开放染色质和转录序列使用最新的染色质构象捕获技术(Hi-C),转座酶易接触的染色质采用高通量测序(ATAC-seq)以及RNA测序在4种具有功能的不同神经细胞中展开。得到了成千上万的远距离的调控元件与启动子互作,并将调控元件与靶标基因进行关联从而揭示疾病中可能存在的失调过程。最后,研究人员使用了基因敲除技术(CRISPR)在人类兴奋性神经元细胞中验证了CDK5RAP3, STRAPDRD2三个基因的转录受到物理上与其接触的增强子调控。

据介绍,基因调控元件上的突变与多种复杂的神经精神疾病有关。然而,由于调控元件的调控功能具有细胞特异性并且识别其所调控的基因具有一定的困难。

 

附:英文原文

Title: Mapping cis -regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes

Author: Michael Song, Xiaoyu Yang, Xingjie Ren, Lenka Maliskova, Bingkun Li, Ian R. Jones, Chao Wang, Fadi Jacob, Kenneth Wu, Michela Traglia, Tsz Wai Tam, Kirsty Jamieson, Si-Yao Lu, Guo-Li Ming, Yun Li, Jun Yao, Lauren A. Weiss, Jesse R. Dixon, Luke M. Judge, Bruce R. Conklin, Hongjun Song, Li Gan, Yin Shen

Issue&Volume: Volume 51 Issue 8

Abstract: Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.

DOI: 10.1038/s41588-019-0472-1

Source:https://www.nature.com/articles/s41588-019-0472-1

期刊信息

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:25.455
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》:Volume 51 Issue 8