Dissecting the epigenome dynamics in human immune cells upon viral and chemical exposure by multimodal single-cell profiling

Environmental and pathogen exposure can 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 comprising 271,299 cells and 319,420 candidate regulatory elements from individuals exposed to HIV-1, COVID-19, Influenza virus, organophosphates, as well as healthy controls. Our longitudinal HIV cohort reveals epigenetic signatures of T cell exhaustion manifested in changes in the accessibility at binding sites for the FOXP family transcription factors. Upon severe exposure to SARS-Cov2 we identified changes in chromatin accessibility manifesting in a regulatory switch in cytokine networks characterized by the downregulation of the NF-{kappa}B motif family, alongside concordant changes in AP-1 and IRF factor networks in CD14+ classical monocytes. By integrating single-cell profiles of DNA methylation from matched samples, we created a multimodal epigenome atlas of human immune cell 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, where BATF, AP-1, and ETS motifs exhibit significant epigenetic covariance across both epigenomic layers. Finally, by linking potentially regulatory DNA methylation signatures to changes in chromatin accessibility in monocytes, we observe that severe COVID-19 involves selective, multiomics remodeling of epigenetic profiles at TF binding sites manifested in concordant DNA methylation and accessibility dynamics at inflammation-associated regulatory TFs.