Abstract
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.
Highlights
The endoplasmic reticulum (ER) is a large cellular organelle that is involved in protein processing, lipid metabolism, and calcium storage
A cell responds to ER stress with the unfolded protein response (UPR), which consists of three main signaling branches, IRE1, ATF6 and PERK [1]
TM is a commonly used pharmacological agent used to experimentally induce ER stress in mouse embryonic fibroblasts (MEFs) [16] and produces a strong transcriptional response to ER stress that models the ER stress that can occur during disease
Summary
The endoplasmic reticulum (ER) is a large cellular organelle that is involved in protein processing, lipid metabolism, and calcium storage. Numerous studies have demonstrated that altering ER stress responses in the mouse, either pharmacologically or genetically, has profound effects on disease outcome This has been demonstrated in different diseases, such as type 2 diabetes, certain forms of cancer, and neurodegenerative diseases. In a form of familial amyotrophic lateral sclerosis, a neurodegenerative motor neuron disease caused by mutations in SOD1, ER stress pathways are activated, but different genetic alterations to the PERK pathway can ameliorate [5] or accelerate [6] the disease. These experimental genetic examples are a proof-of-principle that genetic variation in ER stress response may modify the outcome of certain diseases
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