219B Poster - 01. Cell Stress and cell death
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Katie Owings; Clement Chow

Affiliation: University of Utah

Keywords:
g. unfolded protein response; d. histone variants and modifications

Organisms face many stressors, and an ongoing challenge is understanding how an individual can respond to numerous insults over a lifetime. The accumulation of misfolded proteins results in cellular stresses, including endoplasmic reticulum (ER) stress. Many studies examine the ER stress response in isolation. In reality, cellular stresses rarely occur in isolation but often in the context of other stresses. Little is known about ER stress preconditioning, whereby conditioning with low levels of stress alters the ability to withstand subsequent ER stress. This project aims to use natural genetic variation to characterize ER stress preconditioning and its underlying mechanisms.

I began with an ER stress preconditioning screen that utilized the 200 Drosophila Genetic Reference Panel (DGRP) strains. Flies were subjected to heat shock (or no heat shock control), allowed to recover, placed on tunicamycin to induce ER stress until death, and survival was measured. Different genetic backgrounds led to a striking range in phenotypic responses to ER stress preconditioning, ranging from dying half as fast to 4.5 times faster with preconditioning than with no preconditioning. A genome-wide association study revealed that histone H3-K4 methylation is a solid potential mechanism of ER stress preconditioning. Several candidate modifiers have known roles in histone methylation. H3-K4 methylation marks promoters at transcribed genes and may play a role in transcriptional regulation. Two top modifiers, Pdp1 and TfIIA-L, are general transcription factors associated with RNA polymerase II. These hits solidify a potential role of transcriptional regulation underlying ER stress preconditioning. RNAseq was performed in the phenotypically extreme DGRP strains at different points in the preconditioning protocol to identify potential predictive gene expression signatures. Differentially expressed genes indicate a potential role of immune genes in ER stress preconditioning.

An effective ER stress response is critical for healthy development and aging. Disruptions in this response have been implicated in multiple human diseases, from diabetes to neurodegeneration. Understanding how previous stress events influence the ER stress response will provide insight into this pathway's fundamental biology and have important implications for therapeutic development.