title: Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling.
abstract: Synergistic activation of inflammatory cytokine genes by interferon-γ (IFN-γ) and Toll-like receptor (TLR) signaling is important for innate immunity and inflammatory disease pathogenesis. Enhancement of TLR signaling, a previously proposed mechanism, is insufficient to explain strong synergistic activation of cytokine production in human macrophages. Rather, we found that IFN-γ induced sustained occupancy of transcription factors STAT1, IRF-1, and associated histone acetylation at promoters and enhancers at the TNF, IL6, and IL12B loci. This priming of chromatin did not activate transcription but greatly increased and prolonged recruitment of TLR4-induced transcription factors and RNA polymerase II to gene promoters and enhancers. Priming sensitized cytokine transcription to suppression by Jak inhibitors. Genome-wide analysis revealed pervasive priming of regulatory elements by IFN-γ and linked coordinate priming of promoters and enhancers with synergistic induction of transcription. Our results provide a synergy mechanism whereby IFN-γ creates a primed chromatin environment to augment TLR-induced gene transcription.
authors.affiliation: Arthritis and Tissue Degeneration Program and Genomics Center, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiao
authors.forename: Eugenia G
authors.initials: EG
authors.lastname: Giannopoulou
authors.forename: Chun Hin
authors.initials: CH
authors.lastname: Chan
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Shiaoching
authors.initials: S
authors.lastname: Gong
authors.forename: Janice
authors.initials: J
authors.lastname: Chen
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation; D006657:Histones / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014158:Transcription, Genetic; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D006657:Histones; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051193:Toll-Like Receptors; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma; D053612:Janus Kinases; D012319:RNA Polymerase II