A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV

Abstract

Summary: Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During HIV-1 infection, human dendritic cells (DCs) can detect the virus through an innate sensing pathway, leading to antiviral interferon and DC maturation. Here, we develop an iterative experimental and computational approach to map the HIV-1 innate response circuitry in monocyte-derived DCs (MDDCs). By integrating genome-wide chromatin accessibility with expression kinetics, we infer a gene regulatory network that links 542 transcription factors with 21,862 target genes. We observe that an interferon response is required, yet insufficient, to drive MDDC maturation and identify PRDM1 and RARA as essential regulators of the interferon response and MDDC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting complexity and cooperativity in the regulatory circuit controlling the response to infection. : Pathogen sensing leads to host transcriptional reprogramming to protect against infection. However, it is unclear how transcription factor activity is coordinated across the genome. Johnson et al. integrate chromatin accessibility and gene expression data to infer and validate a gene regulatory network that directs the innate immune response to HIV. Keywords: network inference, DNA sensing, innate signaling, cGAS, STING, IRF3, NF-κB, chromatin modification, ATAC-seq, RNA-seq