生物
染色质
增强子
基因
诱导多能干细胞
遗传学
嘉雅宠物
表观遗传学
清脆的
计算生物学
转录组
电池类型
转录因子
DNA甲基化
染色质重塑
胚胎干细胞
基因表达
细胞
作者
Michael Song,Xiaoyu Yang,W Greenleaf,Lenka Maliskova,Bingkun Li,Ian Jones,Chao Wang,Fadi Jacob,Ken Wu,Michela Traglia,Tsz Wai Tam,Kirsty Jamieson,Shaoping 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
出处
期刊:Nature Genetics
[Springer Nature]
日期:2019-07-31
卷期号:51 (8): 1252-1262
被引量:143
标识
DOI:10.1038/s41588-019-0472-1
摘要
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. An integrative three-dimensional genomic and transcriptional profiling of four human neural cell types links regulatory elements to their target genes and elucidates the function of noncoding variants in neuropsychiatric disorders.
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