title: BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs.
abstract: 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.
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sadler
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria 3800, Australia; Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Parkville 3053, Australia;
authors.forename: Fernando J
authors.identifier: http://orcid.org/0000-0003-3885-8777
authors.initials: FJ
authors.lastname: Rossello
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: James A
authors.initials: JA
authors.lastname: Deane
authors.affiliation: Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China;
authors.forename: Xiangliang
authors.initials: X
authors.lastname: Yuan
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia;
authors.forename: Aaron T
authors.identifier: http://orcid.org/0000-0002-0196-1570
authors.initials: AT
authors.lastname: Irving
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-8964-4456
authors.initials: M
authors.lastname: Kaparakis-Liaskos
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gantier
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia;
authors.forename: Hangjie
authors.initials: H
authors.lastname: Ying
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Yim
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Victoria 3010, Australia;
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Hartland
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Notini
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia;
authors.forename: Suzan
authors.initials: S
authors.lastname: de Boer
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: White
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.affiliation: Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 311121, China;
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; The Kinghorn Cancer Centre, Garvan Institute, Sydney 2010, Australia; and.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: Department of Clinical Haematology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia; Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 311121, China; dakang.xu@mimr-phi.org.
authors.forename: Dakang
authors.initials: D
authors.lastname: Xu
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D031541:Fluorescence Resonance Energy Transfer; D006655:Histone Deacetylases / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse; D006655:Histone Deacetylases
keywords: chromatin structure; inflammation; transcriptional regulation