Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts

Abstract

AbstractCis-regulatory elements (CREs) control gene transcription dynamics across cell types and in response to the environment. In asthma, multiple immune cell types play an important role in the inflammatory process. Genetic variants in CREs can also affect gene expression response dynamics and contribute to asthma risk. However, the regulatory mechanisms underlying control of transcriptional dynamics across different environ-mental contexts and cell-types at single cell resolution remains to be elucidated. To resolve this question, we performed scATAC-seq in activated peripheral blood mononuclear cells (PBMC) from children with asthma with phytohemagglutinin (PHA) or lipopolysaccharide (LPS), and treated with dexamethasone (DEX), an anti-inflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment and cell-type specific transcription factors that drive changes in both gene expression mean and variability. We observed strong positive linear dependence between motif response and their target gene expression changes, but negative in variability changes. This result suggests that an in-crease of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs followed by computational fine-mapping of eQTL signals from a pediatric asthma cohort. We found that eQTLs were highly enriched in peaks with response motifs and refined the credible set of several asthma risk genes. In conclusion, scATAC-seq enhances the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.