Document Type

Article

Publication Date

1-1-2020

Publication Title

PLoS Genet

Keywords

JMG, Animals, Chromatin, Chromatin Assembly and Disassembly, Kidney, Kruppel-Like Transcription Factors, Liver, Lung, Male, Mice, Organ Specificity, Phosphatidylinositol 3-Kinases, Quantitative Trait Loci

JAX Source

PLoS Genet . 2020 Jan 21;16(1):e1008537.

Volume

16

Issue

1

First Page

1008537

Last Page

1008537

ISSN

1553-7404

PMID

31961859

DOI

10.1371/journal.pgen.1008537

Grant

This work was funded by grants from the National Institute of Environmental Health Sciences (NIEHS; https://www.niehs.nih.gov/index.cfm) (R01-ES023195 to IR, TSF, and GEC and P30- ES025128), with GRK and WV funded by grants from the National Institute of General Medical Sciences (NIGMS; https://www.nigms.nih.gov) (R01-GM104125 and R35-GM127000 to WV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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.

Comments

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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