The Genetic Architecture of the Genome-Wide Transcriptional Response to ER Stress in the Mouse

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.
Author Summary Genetic variation among individuals can greatly impact the severity of disease outcomes. To understand the effects of different genetic backgrounds on disease presentation, we focused on ER stress, an important cellular stressor that impacts many human diseases. We examined how genetic variation affects ER stress response, at the RNA level, in eight laboratory mouse strains and their hybrid progeny. We find that each mouse strain responds in a unique way to ER stress, and we characterized the patterns of genetic variation that underlie the differences in ER stress response between the strains. We find that the strains show major differences in their inflammatory response to ER stress, a critical component to disease. The results of this study are important for understanding potential ways in which genetic variation in ER stress response could impact disease, and lays the groundwork for future studies in human patients.