of Philosophy Department

dissertationThe endoplasmic reticulum (ER) stress response is the cellular response to misfolded proteins accumulated in the ER, which entails a large transcriptional response that attempts to return the cell to homeostasis called the unfolded protein response (UPR). Despite the UPR being a conserved cellular process, studies have demonstrated the UPR to be highly variable dependent on genetic background in multiple organisms. This dissertation aims to better understand the genetic mechanisms that underlie the variability within the ER stress response. Chapter 2 studies the cis- and trans- mechanisms involved in the ER stress response. We utilized different strains of an in vivo mouse model and their F1s to identify and quantify context-specific cis- and trans- regulatory mechanisms that underlie the variable transcriptional response to misfolded proteins. We found hundreds of genes that respond to ER stress in a tissue- and genotype-dependent manner. The majority of regulatory mechanisms that underlie these variable transcriptional responses are driven by cis- regulatory variation and are unique to a given tissue or ER stress state. Chapter 3 studies one potential cis- regulatory mechanism through which natural genetic variation can underlie the variable ER stress response. We created a pipeline to identify potential binding sites of the three main transcription factors of the UPR. We quantified how much genetic variation is within these sites known to influence gene expression in multiple human tissues. Finally, we utilized both expression and iv sequencing data from human cell lines experiencing ER stress to perform an eQTL analysis. With this, we identify thousands of SNPs that associate with variable changes in gene expression post-ER stress, with many of these falling within putative binding sites. The results of both of these studies push forward our understanding of how genetic variation can impact the ER stress response. The first study uses a mouse model to characterize the patterns of cis- and trans- mechanisms involved in the ER stress response. The second study further explores how one specific cis- mechanism, TF binding, can potentially underlie the ER stress variability seen in the human population