Synergistic Activation of Inflammatory Cytokine Genes by Priming of Regulatory DNA Elements for Increased Transcription in Response to TLR Signaling

Synergistic activation of inflammatory cytokine genes by IFN-gamma and TLR signaling is important for innate immunity and inflammatory disease pathogenesis, but underlying mechanisms are not known. By obtaining over three billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of human primary monocytes under IFN-gamma-priming and TLR stimulation. We found that IFN-gamma induced genome-wide sustained occupancy of STAT1, IRF-1 and associated histone acetylation at TSS-proximal and distal regulatory elements and provided a synergy mechanism whereby IFN-gamma creates a primed chromatin environment to augment TLR-induced gene transcription, which suggest therapeutic approaches that selectively target priming mechanisms. Examination and comparison of the changes in TF binding and histone modification in human primary monocytes under different conditions.