The dynamic effec of genetic variation on the in vivo ER stress transcriptional response in different tissues

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 (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), 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 ER 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 ER 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 ER 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 ER stress response. Overall design: Examination of both control and TM treated livers and kidneys of B6, CAST, and F1 hybrid mice.

基因表达的遗传调控在不同组织类型与个体间差异显著，且极易受环境因素影响。诸多遗传变异在健康对照条件下可能表现为沉默效应，而在疾病应激状态下甚至会产生相反的作用。本研究采用体内小鼠模型，探究不同组织中遗传变异的效应如何随细胞应激发生动态改变。当错误折叠的蛋白质在内质网（Endoplasmic reticulum, ER）中聚集时，会引发内质网应激。该应激会激活未折叠蛋白反应（Unfolded Protein Response, UPR）——一类旨在恢复细胞稳态的大规模转录应答程序。尽管这一转录应答属于保守的基础细胞过程，但在不同遗传背景下其表现存在高度异质性，因此成为研究遗传变异动态效应的理想模型系统。本研究旨在更深入地解析：在内质网应激存在与缺失的两种情境下，遗传变异如何调控不同组织的基因表达。通过使用不同小鼠品系及其F1杂交后代，我们还能够识别出驱动可变转录应答的、具有情境特异性的顺式（cis-）与反式（trans-）调控变异。研究发现，数百个基因对ER应激的应答呈现组织依赖性和/或基因型依赖性特征。我们鉴定出的绝大多数调控效应均以顺式方式发挥作用，而这些效应正是导致内质网应激应答与组织特异性转录应答存在差异的核心原因。本研究证实，未来的相关研究需纳入多组织中的环境应激因素，方能更清晰地阐明特定遗传因子在诸如内质网应激应答等基础生物通路中的作用机制。实验整体设计：对B6、CAST及F1杂交小鼠的肝脏与肾脏样本（包含对照组与TM处理组）开展检测分析。