权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating the co-transcriptional impact of genetic variation on gene regulation and disease

研究遗传变异对基因调控和疾病的共转录影响

基本信息

批准号：
10380133
负责人：
Yang Li
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380133
关键词：
ATAC-seq Affect Atrial Fibrillation Automobile Driving Belief Cardiac Cardiac Myocytes Cells ChIP-seq Collaborations Complex Complex Genetic Trait DNA Polymerase II DNA Sequence Data Disease Enhancers Etiology Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Genomics Genotype-Tissue Expression Project Goals Grant Heart Human Genome Individual International Introns Link Maps Measures Messenger RNA Methods Molecular Names Phenotype Play Polyadenylation Promoter Regions Protein Isoforms Quantitative Trait Loci RNA RNA Splicing Regulation Regulator Genes Role Series Signal Transduction Spliced Genes Testing Transcript Transcription Elongation Transcription Initiation Transcriptional Regulation Untranslated RNA Variant Work cell type computer studies epigenome genetic element genetic variant genome wide association study induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight lymphoblastoid cell line mRNA Expression novel promoter trait transcriptome sequencing

项目摘要

Abstract Regulatory variation plays a central role in the genetics of complex traits; however, it remains challenging to determine which genes and regulatory mechanisms are affected. While large international collaborations have prioritized understanding how enhancer and promoter regions control gene expression, there remains a gap in our understanding of how genetic elements outside enhancers and promoters impact gene regulation. We propose to use a panel of 70 unrelated HapMap Yoruba lymphoblastoid cell lines (LCLs) to study the mechanisms by which genetic variation impact gene regulation independent of enhancers and promoters. We will further use the iPSCs (induced pluripotent stem cells) and derived cardiomyocytes that we have recently established from these 70 lines to study the effects of the same variants in multiple different cell-types. Recently, we found a class of expression quantitative trait loci (QTLs) variants that affect gene expression as measured by RNA-seq, but that do not show any signal of affecting enhancer or promoter function. We named these variants post-transcription initiation expression QTLs (piQTLs), reflecting our belief that piQTLs function independently of enhancers and promoters. Our data suggest that piQTLs may contribute up to 1/3 of all eQTLs, implying that they explain a considerable fraction of the genetic effects on gene expression levels. Our data also imply that the vast majority of genetic variants that affect RNA splicing (sQTLs) function independently of enhancers and promoters. Because sQTLs are a major link between genetic variation and complex traits, we propose that genetic variants outside enhancers and promoters may contribute substantially to complex traits and disease. In the project, we propose four distinct co-transcriptional mechanisms that may drive piQTLs and/or sQTLs, and we propose a series of analyses to quantify the relative contributions of these mechanisms. We will evaluate the role of each of these proposed mechanisms in LCLs, iPSCs and cardiomyocytes. We will use genome-wide association study (GWAS) data to quantify the contribution of these mechanisms to complex traits and disease. We will focus on cardiac traits for which our data in cardiomyocytes can help us tease putative causal molecular mechanisms apart. At the conclusion of this project we will have thoroughly characterized a class of variants that contribute to the genetic of complex traits independently of enhancers and promoters.

摘要调控变异在复杂性状的遗传学中起着核心作用;然而，确定哪些基因和调控机制受到影响具有挑战性。而大型国际合作优先考虑理解增强子和启动子区域如何控制基因表达，我们对基因元件如何在细胞外表达的理解仍然存在差距。增强子和启动子影响基因调控。我们建议使用70个无关HapMap 约鲁巴淋巴母细胞系（LCL）研究遗传变异影响基因的机制独立于增强子和启动子的调节。我们将进一步使用iPSC（诱导多能干细胞）和衍生的心肌细胞，我们最近已经建立了从这70个线，以研究相同变体在多种不同细胞类型中的作用。最近，我们发现了一类影响基因表达的表达数量性状位点（QTL）变异，通过RNA-seq测量，但不显示任何影响增强子或启动子功能的信号。我们命名这些变体转录后起始表达QTL（piQTL），反映了我们的信念，独立于增强子和启动子起作用。我们的数据表明，piQTL可能贡献高达1/3的所有的eQTL，这意味着他们解释了相当一部分的基因表达水平的遗传效应。我们的数据还表明，绝大多数影响RNA剪接（sQTL）功能的遗传变异独立于增强子和启动子。因为sQTL是遗传变异和复杂的性状，我们提出，增强子和启动子以外的遗传变异可能会大大有助于 to complex复杂traits性状and disease疾病. 在这个项目中，我们提出了四种不同的共转录机制，可能驱动piQTL和/或sQTL，我们提出了一系列的分析来量化这些机制的相对贡献。我们将评估这些提出的机制中的每一个在LCL、iPSC和心肌细胞中的作用。我们将使用全基因组关联研究（GWAS）数据来量化这些机制对复杂性的贡献。性状和疾病。我们将专注于心脏特征，我们在心肌细胞中的数据可以帮助我们梳理假定的因果分子机制分开。在这个项目的结论，我们将有彻底的特点，一类变种，有助于独立于增强子和启动子的复杂性状的遗传。