ABSTRACT
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.
Subject(s)
Dendritic Cells/metabolism , Gene Regulatory Networks , HIV-1/immunology , Immunity, Innate/genetics , Monocytes/metabolism , Cell Differentiation , Chromatin/metabolism , Dendritic Cells/virology , Female , Gene Expression Regulation , HEK293 Cells , HIV Infections/immunology , HIV Infections/virology , Humans , Interferon Type I/metabolism , Male , Monocytes/virology , Promoter Regions, Genetic/genetics , Retinoic Acid Receptor alpha/metabolism , Transcription Factors/metabolism , Transcriptome/geneticsABSTRACT
We have generalized the derivation of genetic-interaction networks from quantitative phenotype data. Familiar and unfamiliar modes of genetic interaction were identified and defined. A network was derived from agar-invasion phenotypes of mutant yeast. Mutations showed specific modes of genetic interaction with specific biological processes. Mutations formed cliques of significant mutual information in their large-scale patterns of genetic interaction. These local and global interaction patterns reflect the effects of gene perturbations on biological processes and pathways.
Subject(s)
Mutation/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Genes, Fungal/genetics , Genetics , Genotype , PhenotypeABSTRACT
We investigated the organization of interacting proteins and protein complexes into networks of modules. A network-clustering method was developed to identify modules. This method of network-structure determination was validated by clustering known signaling-protein modules and by identifying module rudiments in exclusively high-throughput protein-interaction data with high error frequencies and low coverage. The signaling network controlling the yeast developmental transition to a filamentous form was clustered. Abstraction of a modular network-structure model identified module-organizer proteins and module-connector proteins. The functions of these proteins suggest that they are important for module function and intermodule communication.
