STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages [STAT1_CUT&Tag]

By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages.

Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance.