IRF1 governs the differential interferon-stimulated gene responses in human monocytes and macrophages by regulating chromatin accessibility

Ran Song, Yajing Gao, Igor Dozmorov, Venkat Malladi, Irene Saha, Margaret M. McDaniel, Sreeja Parameswaran, Chaoying Liang, Carlos Arana, Bo Zhang, Benjamin Wakeland, Jinchun Zhou, Matthew T. Weirauch, Leah C. Kottyan, Edward K. Wakeland, Chandrashekhar Pasare

Research output: Contribution to journalArticlepeer-review

Abstract

Myeloid lineage cells use TLRs to recognize and respond to diverse microbial ligands. Although unique transcription factors dictate the outcome of specific TLR signaling, whether lineage-specific differences exist to further modulate the quality of TLR-induced inflammation remains unclear. Comprehensive analysis of global gene transcription in human monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells stimulated with various TLR ligands identifies multiple lineage-specific, TLR-responsive gene programs. Monocytes are hyperresponsive to TLR7/8 stimulation that correlates with the higher expression of the receptors. While macrophages and monocytes express similar levels of TLR4, macrophages, but not monocytes, upregulate interferon-stimulated genes (ISGs) in response to TLR4 stimulation. We find that TLR4 signaling in macrophages uniquely engages transcription factor IRF1, which facilitates the opening of ISG loci for transcription. This study provides a critical mechanistic basis for lineage-specific TLR responses and uncovers IRF1 as a master regulator for the ISG transcriptional program in human macrophages.

Original languageEnglish (US)
Article number108891
JournalCell Reports
Volume34
Issue number12
DOIs
StatePublished - Mar 23 2021

Keywords

  • IRF1
  • IRF3
  • TLR4
  • TLR8
  • chromatin accessibility
  • human PBMCs
  • interferon-stimulated genes
  • macrophages
  • monocytes
  • pioneer transcription factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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