Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation (RNA-seq)

Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. We characterize expression and chromatin state dynamics across three tissues--liver, lung, and kidney--in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 genes and 133 chromatin regions. Also detected were eQTL and cQTL whose allelic effects differed across tissues. Leveraging overlapping measurements of gene expression and chromatin accessibility on the same mice from multiple tissues, we used mediation analysis to identify chromatin and gene expression intermediates of eQTL effects. This analysis demonstrates the complexity of transcriptional and chromatin dynamics and their regulation over multiple tissues, as well as the value of the CC and related genetic resource populations for identifying specific regulatory mechanisms within cells and tissues. Investigation of relationships between genetic variation, chromatin accessibility, and gene expression in lung, liver, and kidney tissue from 47 Collaborative Cross mouse strains by differential analysis between tissues, QTL mapping, and mediation analysis跨组织的基因转录谱在很大程度上由调控元件（regulatory element）的活性所决定，其中多数调控元件对应开放染色质区域。调控元件的活性又会受到遗传变异的调控，进而导致不同个体间转录速率存在差异。然而，这些因素之间的相互作用机制目前仍未被充分阐明。本研究以47株协作杂交（Collaborative Cross, CC）小鼠群体为研究对象，对其肝脏、肺脏与肾脏三种组织的基因表达及染色质状态动态特征进行了表征，并借助表达数量性状位点（expression quantitative trait loci, eQTL）与染色质数量性状位点（chromatin QTL, cQTL）分析上述动态特征的调控机制。研究团队在1101个基因与133个染色质区域中检测到了跨组织等位效应一致的数量性状位点，同时还鉴定出跨组织等位效应存在差异的eQTL与cQTL。本研究利用同一批小鼠多组织的基因表达与染色质可及性的重叠测量数据，通过中介分析（mediation analysis）识别出介导eQTL效应的染色质与基因表达中介因子。上述分析不仅阐明了转录与染色质动态特征及其跨组织调控机制的复杂性，同时验证了CC及相关遗传资源群体在解析细胞与组织内特定调控机制方面的应用价值。本研究通过组织间差异分析、数量性状位点定位以及中介分析，探究了47株协作杂交小鼠的肺脏、肝脏与肾脏组织中遗传变异、染色质可及性与基因表达之间的关联。