Chow Clement Y, Wang Xu, Riccardi David, Wolfner Mariana F, Clark Andrew G
Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
PLoS Genet. 2015 Feb 4;11(2):e1004924. doi: 10.1371/journal.pgen.1004924. eCollection 2015 Feb.
Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. The cellular response to ER stress involves complex transcriptional and translational changes, important to the survival of the cell. ER stress is a primary cause and a modifier of many human diseases. A first step to understanding how the ER stress response impacts human disease is to determine how the transcriptional response to ER stress varies among individuals. The genetic diversity of the eight mouse Collaborative Cross (CC) founder strains allowed us to determine how genetic variation impacts the ER stress transcriptional response. We used tunicamycin, a drug commonly used to induce ER stress, to elicit an ER stress response in mouse embryonic fibroblasts (MEFs) derived from the CC founder strains and measured their transcriptional responses. We identified hundreds of genes that differed in response to ER stress across these genetically diverse strains. Strikingly, inflammatory response genes differed most between strains; major canonical ER stress response genes showed relatively invariant responses across strains. To uncover the genetic architecture underlying these strain differences in ER stress response, we measured the transcriptional response to ER stress in MEFs derived from a subset of F1 crosses between the CC founder strains. We found a unique layer of regulatory variation that is only detectable under ER stress conditions. Over 80% of the regulatory variation under ER stress derives from cis-regulatory differences. This is the first study to characterize the genetic variation in ER stress transcriptional response in the laboratory mouse. Our findings indicate that the ER stress transcriptional response is highly variable among strains and arises from genetic variation in individual downstream response genes, rather than major signaling transcription factors. These results have important implications for understanding how genetic variation impacts the ER stress response, an important component of many human diseases.
当错误折叠的蛋白质在内质网（ER）中积累时，就会发生内质网应激。细胞对内质网应激的反应涉及复杂的转录和翻译变化，这对细胞的存活至关重要。内质网应激是许多人类疾病的主要病因和调节因素。了解内质网应激反应如何影响人类疾病的第一步是确定内质网应激的转录反应在个体之间是如何变化的。八个小鼠协作杂交（CC）创始品系的遗传多样性使我们能够确定遗传变异如何影响内质网应激转录反应。我们使用衣霉素（一种常用于诱导内质网应激的药物）在源自CC创始品系的小鼠胚胎成纤维细胞（MEF）中引发内质网应激反应，并测量它们的转录反应。我们鉴定出数百个在这些基因多样化的品系中对内质网应激反应不同的基因。令人惊讶的是，炎症反应基因在品系之间差异最大；主要的内质网应激反应经典基因在各品系中表现出相对不变的反应。为了揭示这些内质网应激反应品系差异背后的遗传结构，我们测量了源自CC创始品系之间F1杂交子集的MEF对内质网应激的转录反应。我们发现了一层独特的调控变异，只有在内质网应激条件下才能检测到。内质网应激下超过80%的调控变异源自顺式调控差异。这是第一项在实验室小鼠中表征内质网应激转录反应遗传变异的研究。我们的研究结果表明，内质网应激转录反应在品系之间高度可变，并且源于个体下游反应基因的遗传变异，而不是主要的信号转录因子。这些结果对于理解遗传变异如何影响内质网应激反应具有重要意义，内质网应激反应是许多人类疾病的一个重要组成部分。
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