3D promoter architecture re-organization during iPSC-derived neuronal cell differentiation implicates target genes for neurodevelopmental disorders.
3D promoter architecture re-organization during iPSC-derived neuronal cell differentiation implicates target genes for neurodevelopmental disorders.
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iPSC衍生的神经元细胞分化期间的3D启动子结构重组涉及神经发育障碍的靶基因。
DOI：
10.1016/j.pneurobio.2021.102000
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发表时间：
2021-06
影响因子：
6.7
通讯作者：
Grant SFA
中科院分区：
文献类型：
--
作者：
Su C;Argenziano M;Lu S;Pippin JA;Pahl MC;Leonard ME;Cousminer DL;Johnson ME;Lasconi C;Wells AD;Chesi A;Grant SFA
神经发育障碍被认为是由早期大脑发育中断引起的。全基因组关联研究（GWAS）已经确定了数百个与神经发育障碍易感性相关的基因座;然而，哪些非编码变体调节这些基因座上的哪些基因往往不清楚。为了揭示神经元GWAS效应基因，我们使用高分辨率启动子聚焦的Capture-C，ATAC-seq和RNA-seq的组合对诱导多能干细胞衍生的神经元祖细胞（NPC）发育成神经元期间的转录组学，表观基因组学和染色质构象变化进行了综合分析。我们观察到，在NPC到神经元的过渡过程中，基因表达的变化高度依赖于启动子可及性的变化和连接远端顺式调控元件（增强子或沉默子）与发育阶段特异性基因的长程相互作用。这些基因组规模的启动子顺式调节元件图谱涉及454个神经发育障碍相关的，推定的因果变异映射到600个远端目标。这些推定的效应基因显着丰富的参与调节神经元发育和染色质组织的途径，与27%的阶段特异性的方式表达。开放染色质和染色质构象的交叉点揭示了神经元分化过程中发育阶段特异性的基因调控结构，为神经发育障碍的遗传和发育基础的表征提供了丰富的资源。
Neurodevelopmental disorders are thought to arise from interrupted development of the brain at an early age. Genome-wide association studies (GWAS) have identified hundreds of loci associated with susceptibility to neurodevelopmental disorders; however, which noncoding variants regulate which genes at these loci is often unclear. To implicate neuronal GWAS effector genes, we performed an integrated analysis of transcriptomics, epigenomics and chromatin conformation changes during the development from Induced pluripotent stem cell–derived neuronal progenitor cells (NPCs) into neurons using a combination of high-resolution promoter-focused Capture-C, ATAC-seq and RNA-seq. We observed that gene expression changes during the NPC-to-neuron transition were highly dependent on both promoter accessibility changes and long-range interactions which connect distal cis-regulatory elements (enhancer or silencers) to developmental-stage-specific genes. These genome-scale promoter-cis-regulatory-element atlases implicated 454 neurodevelopmental disorder-associated, putative causal variants mapping to 600 distal targets. These putative effector genes were significantly enriched for pathways involved in the regulation of neuronal development and chromatin organization, with 27% expressed in a stage-specific manner. The intersection of open chromatin and chromatin conformation revealed development-stage-specific gene regulatory architectures during neuronal differentiation, providing a rich resource to aid characterization of the genetic and developmental basis of neurodevelopmental disorders.
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影响因子：
46.9
作者：
Ernst J;Kellis M
通讯作者：
Kellis M
影响因子：
11
作者：
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
通讯作者：
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
影响因子：
7.7
作者：
Freire-Pritchett P;Schoenfelder S;Várnai C;Wingett SW;Cairns J;Collier AJ;García-Vílchez R;Furlan-Magaril M;Osborne CS;Fraser P;Rugg-Gunn PJ;Spivakov M
通讯作者：
Spivakov M