Abstract
Pathogen and chemical exposures lead to profound remodeling of the gene-regulatory landscape across human immune cell populations. Here, we present a single-nucleus chromatin accessibility atlas of human immune cells of individuals exposed to HIV-1, COVID-19, Influenza virus, organophosphates as well as healthy controls that provides insights into gene regulation driven by these cell-extrinsic stimuli. This atlas comprises 271,299 cells and 319,420 candidate regulatory elements that exhibit dynamic accessibility associated with gene expression across immune cell states. Our longitudinal HIV cohort reveals epigenetic signatures of T cell exhaustion, manifested in changes in the accessibility of binding sites for the FOXP family transcription factors. We further identified changes in the accessibility of candidate regulatory elements in CD14 monocytes upon SARS-CoV-2 exposure that are associated with a switch in NF-κB to AP-1-based regulation of cytokine networks. By integrating single-cell profiles of DNA methylation from matched samples we created a multimodal epigenome atlas of human immune cells across exposure states using the accessibility-derived candidate regulatory elements. Both modalities exhibit complementary epigenetic signatures at transcription factor binding sites associated with cell state, as exemplified in the process of memory formation in T-cells. Finally, by linking potentially regulatory DNA methylation signatures to changes in chromatin accessibility in monocytes, we identify AP1 motifs exhibiting epigenetic dynamics, indicating selective remodeling in TF networks in severe cases of COVID-19.