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

Jarrod S. Johnson, Nicholas De Veaux, Alexander W. Rives, Xavier Lahaye, Sasha Y. Lucas, Brieuc P. Perot, Marine Luka, Victor Garcia-Paredes, Lynn M. Amon, Aaron Watters, Ghaith Abdessalem, Alan Aderem, Nicolas Manel, Dan R. Littman, Richard Bonneau, Mickaël M. Ménager

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)914-931.e9
JournalCell Reports
Volume30
Issue number3
DOIs
StatePublished - Jan 21 2020

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Keywords

  • ATAC-seq
  • cGAS
  • chromatin modification
  • DNA sensing
  • innate signaling
  • IRF3
  • network inference
  • NF-κB
  • RNA-seq
  • STING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Johnson, J. S., De Veaux, N., Rives, A. W., Lahaye, X., Lucas, S. Y., Perot, B. P., Luka, M., Garcia-Paredes, V., Amon, L. M., Watters, A., Abdessalem, G., Aderem, A., Manel, N., Littman, D. R., Bonneau, R., & Ménager, M. M. (2020). A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV. Cell Reports, 30(3), 914-931.e9. https://doi.org/10.1016/j.celrep.2019.12.054