Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Abstract

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

Transcription factor regulation of eQTL activity across individuals and tissues

“…allele-specific gene expression in three cell lines, discovering 979 genes with GxE effects, of which were also found to have a GxE interaction by a previous study [12]. We overlapped our dual evidence TF-eQTL genes with these replicated GxE interacting genes and found overlaps (OR = 2.67, Fisher's exact test p = 1.4x10 -14 ) [Fig.…”

“…While GxE interactions on human phenotype have been difficult to assess, GxE interactions in relation to gene expression have been studied under various contexts [8,[12][13][14][15][63][64][65]. Overlapping these effects with TF-eQTLs as in our analysis, or even performing TF-eQTL analysis in the environmental exposure datasets themselves, provides mechanistic hypotheses of how environmental effects impact genetic control of gene expression and phenotype.…”

“…We hypothesized that our TF-eQTLs could shed light on mechanisms of gene-by-environment (GxE) interactions that represent environmental conditions that affect genetic control of a phenotype, and altered TF level could be the mechanism by which the environmental condition regulates the genetic effects. In a recent large-scale study, Findley et al tested the effects of 14 environmental treatments on allele-specific gene expression in three cell lines, discovering 979 genes with GxE effects, of which were also found to have a GxE interaction by a previous study [12]. We overlapped our dual evidence TF-eQTL genes with these replicated GxE interacting genes and found 92 overlaps (OR = 2.67, Fisher's exact test p = 1.4x10 -14 ) [Fig.…”

“…Gene-by-environment interaction analysis results were attained from Supplemental Table 4 in Findley et al, [Table 2] [12]. We matched these results by ENSG number with our dual-evidence TF-eQTL genes and used Fisher's exact test to calculate overlap compared to all tested genes in our dataset.…”

“…Further work using computational cell type deconvolution has discovered approximately three thousand GTEx eQTLs whose effects are likely cell-type-specific [6]. Additional context-specific eQTL effects have been assayed in a variety of settings, including during immune stimulation [7,8], cell stress [9,10], cell differentiation [11], and drug or nutrient exposure [12][13][14].…”