Characterizing genetic variation in the regulation of the ER stress response through computational and cis-eQTL analyses.

Misfolded proteins in the endoplasmic reticulum (ER) elicit the ER stress response, a large transcriptional response driven by three well-characterized transcription factors. This transcriptional response is variable across different genetic backgrounds. One mechanism in which genetic variation can lead to transcriptional variability in the ER stress response is through altered binding and activity of the three main transcription factors: XBP1, ATF6, and ATF4. This work attempts to better understand this mechanism by first creating a computational pipeline to identify potential binding sites throughout the human genome. We utilized GTEx datasets to identify cis- eQTLs that fall within predicted transcription factor binding sites (TFBSs). We also utilized the ClinVar database to compare the number of pathogenic versus benign variants at different positions of the binding motifs. Finally, we performed a cis- eQTL analysis on human cell lines experiencing ER stress to identify cis- eQTLs that regulate the variable ER stress response. The majority of these cis- eQTLs are unique to a given condition: control or ER stress. Some of these stress-specific cis- eQTLs fall within putative binding sites of the three main ER stress response transcription factors, providing a potential mechanism by which these cis- eQTLs might be impacting gene expression under ER stress conditions through altered TF binding. This study represents the first cis- eQTL analysis on human samples experiencing ER stress and is a vital step towards identifying the genetic components responsible for the variable ER stress response.