GATA2 decommissioning of enhancers: A mechanism to constrain inflammatory signaling

GATA2 establishes transcriptomes governing hematopoietic stem/progenitor cell development. In progenitors, GATA2 represses inflammatory genes (Il6st and Il6ra) encoding IL6ST/GP130 and IL6RA receptor subunits mediating IL-6 signaling. While IL6ST heterodimerizes with IL6RA, IL-11, IL-27, oncostatin M, and leukemia inhibitory factor receptors, IL6RA heterodimerizes exclusively with IL6ST to confer IL-6 signaling. As GATA2-dependent repression is not well understood, we devised a multi-omics strategy to elucidate mechanisms underlying repression and applied the approach to the cytokine/chemokine receptor gene family. Identifying accessible distal and intronic chromatin sites in GATA2-deficient (GATA2^low), but not wild-type, progenitors unveiled that GATA2 represses Il6st and Il6ra enhancers. GATA2 loss instigates a chromatin transition to increase accessibility, occupancy by the hematopoietic activator PU.1, transcription, and cell signaling capacity. Ablating Il6st enhancers in GATA2^low cells abrogates Il6st expression and IL-6 and IL-27 signaling. Il6ra enhancer loss selectively abrogates Il6ra expression and IL-6 signaling. Thus, GATA2 decommissions enhancers to constrain inflammatory signaling.