Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
G3 (Bethesda). 2022 May 30;12(6). doi: 10.1093/g3journal/jkac104.
The genetic regulation of gene expression varies greatly across tissue-type and individuals and can be strongly influenced by the environment. Many variants, under healthy control conditions, may be silent or even have the opposite effect under diseased stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with cellular stress across different tissues. Endoplasmic reticulum stress occurs when misfolded proteins accumulate in the endoplasmic reticulum. This triggers the unfolded protein response, a large transcriptional response which attempts to restore homeostasis. This transcriptional response, despite being a conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study the dynamic effects of genetic variation. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of endoplasmic reticulum stress. The use of different mouse strains and their F1s allow us to also identify context-specific cis- and trans- regulatory variation underlying variable transcriptional responses. We found hundreds of genes that respond to endoplasmic reticulum stress in a tissue- and/or genotype-dependent manner. The majority of the regulatory effects we identified were acting in cis-, which in turn, contribute to the variable endoplasmic reticulum stress- and tissue-specific transcriptional response. This study demonstrates the need for incorporating environmental stressors across multiple different tissues in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the endoplasmic reticulum stress response.
基因表达的遗传调控在组织类型和个体之间差异很大，并且可以受到环境的强烈影响。在健康对照条件下，许多变体可能是沉默的，甚至在患病应激条件下会产生相反的效果。本研究使用体内小鼠模型来研究遗传变异的影响如何随着细胞应激在不同组织中变化。内质网应激发生在错误折叠的蛋白质在内质网中积累时。这会触发未折叠蛋白反应，这是一个试图恢复体内平衡的大型转录反应。尽管这种转录反应是一个保守的基本细胞过程，但在不同的遗传背景下高度可变，使其成为研究遗传变异动态效应的理想系统。在这项研究中，我们试图更好地了解遗传变异如何在存在和不存在内质网应激的情况下改变组织中的表达。使用不同的小鼠品系及其 F1 杂种允许我们还鉴定潜在的组织特异性顺式和反式调节变异，这些变异是可变转录反应的基础。我们发现了数百个在组织和/或基因型依赖性方面对内质网应激有反应的基因。我们鉴定的大多数调节作用都是顺式作用的，这反过来又导致内质网应激和组织特异性转录反应的可变。这项研究表明，未来的研究需要在多个不同组织中纳入环境应激源，以更好地阐明任何特定遗传因素在基本生物学途径（如内质网应激反应）中的作用。
