Restricting genomic actions of innate immune mediators on fetal hematopoietic progenitor cells
Vu L. Tran,
Peng Liu,
Koichi R. Katsumura,
Erin Kim,
Bjorn M. Schoff,
Kirby D. Johnson,
Emery H. Bresnick
Affiliations
Vu L. Tran
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Peng Liu
Department of Biostatistics and Biomedical Informatics, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Koichi R. Katsumura
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Erin Kim
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Bjorn M. Schoff
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Kirby D. Johnson
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Emery H. Bresnick
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Corresponding author
Summary: Innate immune signaling protects against pathogens, controls hematopoietic development, and functions in oncogenesis, yet the relationship between these mechanisms is undefined. Downregulating the GATA2 transcription factor in fetal hematopoietic progenitor cells upregulates genes encoding innate immune regulators, increases Interferon-γ (IFNγ) signaling, and disrupts differentiation. We demonstrate that deletion of an enhancer that confers GATA2 expression in fetal progenitors elevated Toll-like receptor (TLR) TLR1/2 and TLR2/6 expression and signaling. Rescue by expressing GATA2 downregulated elevated TLR signaling. IFNγ amplified TLR1/2 and TLR2/6 signaling in GATA2-deficient progenitors, synergistically activating cytokine/chemokine genes and elevating cytokine/chemokine production in myeloid cell progeny. Genomic analysis of how innate immune signaling remodels the GATA2-deficient progenitor transcriptome revealed hypersensitive responses at innate immune genes harboring motifs for signal-dependent transcription factors and factors not linked to these mechanisms. As GATA2 establishes a transcriptome that constrains innate immune signaling, insufficient GATA2 renders fetal progenitor cells hypersensitive to innate immune signaling.
