Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Faculty of Biology, Division of Evolutionary Biology, Ludwig-Maximilian University of Munich, Munich, Germany.
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Cell. 2018 Jun 14;173(7):1796-1809.e17. doi: 10.1016/j.cell.2018.04.018. Epub 2018 May 17.
Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.
非编码遗传变异是表型多样性的主要驱动因素，它允许我们研究控制基因表达的机制。在这里，我们系统地研究了来自 5 个品系小鼠的超过 5000 万个变异对静止和激活巨噬细胞中 mRNA、新生转录本、转录起始位点和转录因子结合的影响。我们观察到与不同分子途径相关的显著差异。评估遗传变异为塑造决定谱系的因子结合提供了约 100 个 TF 的证据。出乎意料的是，相当一部分品系特异性因子结合不能用局部突变来解释。将基因组特征与染色质相互作用数据整合在一起，提供了数百个与转录因子结合和基因表达差异相关的连接顺式调控域的证据。该系统和超过 250 个数据集为研究遗传变异如何影响细胞表型建立了一个重要的新资源。
