Epigenetic variation impacts ancestry-associated differences in the transcriptional response to influenza infection

Abstract

SummaryHumans display remarkable inter-individual variation in immune response when exposed to identical immune challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we carried out in-depth genetic, epigenetic, and transcriptional profiling on primary macrophages derived from a panel of European and African-ancestry individuals before and after infection with influenza A virus (IAV). We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to IAV across individuals, and that ancestry-associated differences in gene expression are tightly coupled with variation in enhancer activity. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape are genetically controlled, even more so than variation in gene expression. Lastly, we show that among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, the remaining corresponding to genetic variants that impact one or more epigenetic marks, which stresses the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.

Shaping immunity: The influence of natural selection on population immune diversity

“…Epigenetic mechanisms have been shown to play a central role in the regulation of immune responses to bacterial and viral pathogens. [79][80][81][82][83][84][85][86][87][88][89] Thus, it is likely that variation in epigenetic profiles across individuals and populations considerably contributes to population variation in innate immune responses and susceptibility to disease. The field of population epigenomics has primarily concentrated on the differences in DNA methylation levels among individuals.…”

“…Recently, however, the scope has expanded to include a wider range of epigenetic modifications and their complex interactions with gene regulation. [89][90][91][92] For example, Aracena et al performed an in-depth genetic, epigenetic, and transcriptional profiling of primary macrophages derived from European-and African-ancestry individuals before and after IAV infection. 89 These data revealed that baseline epigenetic profiles are strongly predictive of the transcriptional response to IAV across individuals, supporting the concept that changes in gene expression in response to IAV infection are, in part, influenced by the pre-existing epigenetic states of an individual's cells.…”

“…Despite meaning "above the genes", epigenetic variation across individuals is influenced by genetic variation. 59,[89][90][91][92][93][94][95] In macrophages, for example, ~52% of population variation in chromatin accessibility is explained by differences in allele frequencies of genetic variants associated with chromatin accessibility levels. 89 This fraction rises to up to 65% for DNA methylation differences, 89,92 revealing that genetic ancestry-associated diversity in the epigenetic landscape is strongly genetically controlled.…”

“…59,[89][90][91][92][93][94][95] In macrophages, for example, ~52% of population variation in chromatin accessibility is explained by differences in allele frequencies of genetic variants associated with chromatin accessibility levels. 89 This fraction rises to up to 65% for DNA methylation differences, 89,92 revealing that genetic ancestry-associated diversity in the epigenetic landscape is strongly genetically controlled. Comparatively, 13%-54% of population variation in gene expression has been explained by genetic factors, [16][17][18]89 underscoring the fact that, for some cell types, epigenetic variation is even more dependent on underlying genetics than gene expression variation.…”

“…89 This fraction rises to up to 65% for DNA methylation differences, 89,92 revealing that genetic ancestry-associated diversity in the epigenetic landscape is strongly genetically controlled. Comparatively, 13%-54% of population variation in gene expression has been explained by genetic factors, [16][17][18]89 underscoring the fact that, for some cell types, epigenetic variation is even more dependent on underlying genetics than gene expression variation.…”