Hematopoietic Progenitor Cell Genome Sensing of Inflammation [RNA-Seq]

Genomes must adapt dynamically to alterations in the signaling milieu, including acute and chronic inflammation that transiently or permanently disrupt genome function. We investigated this problem with a human disorder caused by heterozygous mutations in GATA2, encoding a hematopoietic stem/progenitor cell regulator. GATA2 deficiency causes bone marrow failure in humans and mice and predisposes to leukemia in humans. GATA2-deficient murine progenitors are hypersensitive to Toll-Like Receptor (TLR)- and interferon-g-mediated inflammatory signaling, and downregulating the cell type-specific transcription factor PU.1 reduced TLR1/2- and IFNg-induced transcriptional responses. Genome sensing of inflammation involved inflammation-dependent recruitment of PU.1 to chromatin and PU.1 pre-occupying specific loci. Motifs for RUNX developmental regulators were enriched at TLR1/2-IFNg-activated genes in GATA2-deficient progenitors. Contrasting with the paradigm in which GATA2 and RUNX1 function cooperatively, their opposing activities were vital for integrating signaling and transcriptional mechanisms to endow a progenitor genome with the capacity to sense the inflammatory environment.