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


Autoři: Gregory R. Keele aff001;  Bryan C. Quach aff001;  Jennifer W. Israel aff002;  Grace A. Chappell aff005;  Lauren Lewis aff005;  Alexias Safi aff006;  Jeremy M. Simon aff002;  Paul Cotney aff002;  Gregory E. Crawford aff006;  William Valdar aff002;  Ivan Rusyn aff005;  Terrence S. Furey aff002
Působiště autorů: Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff001;  Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff002;  The Jackson Laboratory, Bar Harbor, Maine, United States of America aff003;  Center for Omics Discovery and Epidemiology, Research Triangle Institute (RTI) International, Research Triangle Park, North Carolina, United States of America aff004;  Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, United States of America aff005;  Department of Pediatrics, Duke University, Durham, North Carolina, United States of America aff006;  Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, United States of America aff007;  Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff008;  Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff009
Vyšlo v časopise: Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008537
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008537

Souhrn

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.

Klíčová slova:

Gene expression – Gene mapping – Gene regulation – Haplotypes – Chromatin – Kidneys – Mammalian genomics – Quantitative trait loci


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