BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 5; pp. 1535 - 1540
• Main Authors: Sadler, Anthony J., Rossello, Fernando J., Yu, Liang, Deane, James A., Yuan, Xiangliang, Wang, Die, Irving, Aaron T., Kaparakis-Liaskos, Maria, Gantier, Michael P., Ying, Hangjie, Yim, Howard C. H., Hartland, Elizabeth L., Notini, Amanda J., de Boer, Suzan, White, Stefan J., Mansell, Ashley, Liu, Jun-Ping, Watkins, D. Neil, Gerondakis, Steve, Williams, Bryan R. G., Xu, Dakang
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.02.2015; National Acad Sciences
• Subjects: Animals; Bacterial Infections - metabolism; Biological Sciences; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation; Cytokines; Enzyme kinetics; Fluorescence Resonance Energy Transfer; Genomics; Histone Deacetylases - metabolism; Homeostasis; Inflammation - metabolism; Kruppel-Like Transcription Factors - metabolism; Leukemia; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Promyelocytic Leukemia Zinc Finger Protein; Real-Time Polymerase Chain Reaction; Signal Transduction; T cell receptors; inflammation; transcriptional regulation; chromatin structure
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1409728112

Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation. Significance Maintaining physiological balance is vital in the primary response to infectious and other stress stimuli to avert damaging inflammation. Delineation of the cell regulatory processes that control inflammatory processes better enable the development of informed strategies to treat associated pathologies. Toward this end, we identify that the promyelocytic leukemia zinc finger (PLZF) transcription factor limits pathogen-induced inflammation. PLZF stabilizes a repressor complex that encompasses histone deacetylase activity, which modifies the state of chromatin. This activity maintains homeostasis by decreasing the scale of induction of select immune response genes. In the absence of PLZF, the chromatin structure is altered, enabling active transcriptional complexes to immediately assemble on gene promoters, resulting in inordinate production of inflammatory cytokines.