| Popis: |
Genetic variation contributes greatly to differences between people, including differences in susceptibility to disease. A critical way that genetic variation influences traits is through impacts on gene regulation. In particular, context-specific gene regulation only visible during certain points in an organism’s development or under specific conditions is likely an important and understudied contributor to trait and disease variation. Using induced pluripotent stem cell-derived chondrogenic cells and in vitro mechanical and cytokine treatments, I characterized a system to study context-specific gene regulation in the lab, with relevance to the joint disease osteoarthritis (OA). First, I used bulk and single cell transcriptional information from iPSC-derived chondrogenic cells (iPSC-chondrocytes) from three individuals subjected to control and mechanical stress conditions used to model OA. From this study, I found that patterns of gene expression that differ between conditions are relevant for gene sets related to joint health and OA. I also found examples of genes that exhibit inter-individual differences in responses to biomechanical strain, potentially representing examples of gene-by-environment interactions in response to perturbations. I expanded this system to survey transcription from iPSC-chondrocytes derived from 22 genotyped individuals under static, biomechanical strain, and inflammatory cytokine conditions. Through this study, I found shared and unique gene expression patterns that are activated in iPSC-chondrocytes in response to the two treatments. I further performed expression quantitative trait locus (eQTL) mapping to correlate genetic variation to gene regulation in each treatment condition. By comparing eQTLs between conditions, I determined a set of dynamic response eQTLs that are only visible in specific environmental contexts and represent the effects of gene-by-environment interactions on gene regulation. This work represents a study of genetic control of gene regulation in a disease-relevant cell type in disease-relevant environmental contexts. |
