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. Overall design: 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