Abstract
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. Here 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, including local-eQTL for Pik3c2g detected in all three tissues but with distinct allelic effects. 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. Based on QTL and mediation analyses over multiple tissues, we propose a causal model for the distal genetic regulation of Akr1e1, a gene involved in glycogen metabolism, through the zinc finger transcription factor Zfp985 and chromatin intermediates. 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.
Highlights
Determining the mechanisms by which genetic variants drive molecular, cellular, and physiological phenotypes has proved to be challenging [1]
The same genetic variants may associate with both molecular events, and these may be connected within the same causal path: a variant that reduces promoter region chromatin accessibility, potentially by affecting transcription factor binding, may lead to reduced expression of that gene
We identify a number of candidate causal mediators of the genetic regulation of gene expression, including a zinc finger protein that helps silence the Akr1e1 gene
Summary
Determining the mechanisms by which genetic variants drive molecular, cellular, and physiological phenotypes has proved to be challenging [1] These mechanisms can be informed by genome-wide experiments that provide data on variations in molecular and cellular states in genotyped individuals. One approach to shed light on these dynamics is to pair complementary datasets from the same individuals and perform statistical mediation analysis (e.g., [3,4,5]), which has increasingly been used in genomics [6] These analyses can identify putative causal relationships rather than correlational interactions, providing meaningful and actionable targets in terms of downstream applications in areas such as medicine and agriculture. More formal integration through statistical mediation analyses has been used to investigate relationships between levels of human biological data, such as distal genetic regulation through local gene expression [10, 11], and eQTL with regulatory elements [12,13,14] and physiological phenotypes, such as cardiometabolic traits [15]
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