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Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation.
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-01-21 , DOI: 10.1371/journal.pgen.1008537
Gregory R Keele 1, 2, 3 , Bryan C Quach 1, 2, 4 , Jennifer W Israel 2 , Grace A Chappell 5 , Lauren Lewis 5 , Alexias Safi 6, 7 , Jeremy M Simon 2 , Paul Cotney 2 , Gregory E Crawford 6, 7 , William Valdar 2, 8 , Ivan Rusyn 5 , Terrence S Furey 2, 8, 9
Affiliation  

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.

中文翻译:


基因表达和染色质可及性的综合 QTL 分析可识别遗传调控的多组织模式。



跨组织的基因转录谱很大程度上是由调控元件的活性决定的,其中大部分对应于可接近染色质的区域。调控元件的活性反过来又受到遗传变异的调节,导致个体之间的转录率存在差异。然而,人们对这些因素之间的相互作用知之甚少。在这里,我们描述了 47 个协作杂交 (CC) 小鼠品系中三个组织(肝、肺和肾)的表达和染色质状态动态,通过表达数量性状位点 (eQTL) 和染色质 QTL 检查这些动态的调节。 cQTL)。检测到 1,101 个基因和 133 个染色质区域的 QTL,其等位基因效应在组织中一致。还检测到 eQTL 和 cQTL,其等位基因效应在不同组织中不同,包括在所有三种组织中检测到的 Pik3c2g 的局部 eQTL,但具有不同的等位基因效应。利用对来自多个组织的同一小鼠的基因表达和染色质可及性的重叠测量,我们使用中介分析来识别 eQTL 效应的染色质和基因表达中间体。基于对多个组织的 QTL 和介导分析,我们提出了一个通过锌指转录因子 Zfp985 和染色质中间体对参与糖原代谢的基因 Akr1e1 进行远端遗传调控的因果模型。该分析证明了转录和染色质动力学的复杂性及其对多个组织的调节,以及 CC 和相关遗传资源群体对于识别细胞和组织内特定调节机制的价值。
更新日期:2020-02-18
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