Characterization of changes in enhancer activity and transcription factor binding following pro-inflammatory cytokine treatments in primary mouse hepatocytes

The cytokines interleukin 1ß and 6 (IL-1ß, IL-6) mediate the systemic acute and chronic inflammatory response. In liver, they both regulate the secretion of acute-phase proteins which curb infection and tissue damage. Using RNA-seq, we show that these cytokines regulate gene transcription in a multifaceted manner to modulate gene expression, leading both to synergistic and antagonistic expression patterns. By mapping changes in enhancer landscape and transcription factor occupancy following cytokine treatment, we show that synergistic gene expression was achieved by cooperation between cytokine-induced transcription factors on the chromatin template. At a subset of enhancers proximal to synergistically-induced acute-phase genes, IL-1ß led to enhancer priming and an increase in STAT3 binding. These effects were mediated by NF-?B and were enhancer-specific rather that influencing the entirety of STAT3 binding. Our findings reveal that STAT3-NF-?B crosstalk at the chromatin template plays a major role in transcriptional regulation during inflammation Overall design: the enhancer mark H3K27ac and various transcription factors were profiled by ChIP-seq following cytokine treatemnts (treatment regimen and replicates specified in sample title, NT is the control samples)