Specific enhancer selection by IRF3, IRF5 and IRF9 is determined by ISRE half-sites, 5 (cid:2) and 3 (cid:2) flanking bases, collaborating transcription factors and the chromatin environment in a combinatorial fashion

IRF3, IRF5 and IRF9 are transcription factors, which play distinct roles in the regulation of antiviral and inflammatory responses. The determinants that mediate IRF-specific enhancer selection are not fully understood. To uncover regions occupied predom-inantly by IRF3, IRF5 or IRF9, we performed ChIP-seq experiments in activated murine dendritic cells. The identified regions were analysed with respect to the enrichment of DNA motifs, the interferon-stimulated response element (ISRE) and ISRE half-site variants, and chromatin accessibility. Using a machine learning method, we investigated the pre-dictability of IRF-dominance. We found that IRF5-dominant regions differed fundamentally from the IRF3- and IRF9-dominant regions: ISREs were rare,

[1]  T. Decker,et al.  A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription , 2019, Nature Communications.

[2]  M. Gale,et al.  IRF5 regulates unique subset of genes in dendritic cells during West Nile virus infection , 2018, Journal of leukocyte biology.

[3]  T. Decker,et al.  Regulatory Networks Involving STATs, IRFs, and NFκB in Inflammation , 2018, Front. Immunol..

[4]  T. Tang,et al.  Interferon Regulatory Factor 9 Structure and Regulation , 2018, Front. Immunol..

[5]  C. Horvath,et al.  Histone H2A.Z Suppression of Interferon-Stimulated Transcription and Antiviral Immunity Is Modulated by GCN5 and BRD2 , 2018, iScience.

[6]  Trevor Siggers,et al.  DNA-binding landscape of IRF3, IRF5 and IRF7 dimers: implications for dimer-specific gene regulation , 2018, Nucleic acids research.

[7]  Baohong Zhang,et al.  B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation , 2018, Front. Immunol..

[8]  Y. Crow,et al.  Faculty Opinions recommendation of Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. , 2017 .

[9]  Xiaodi Wu,et al.  Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF–IRF4 transcription factor complex , 2017 .

[10]  D. Panne,et al.  Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function , 2017, Proceedings of the National Academy of Sciences.

[11]  M. Bulyk,et al.  Transcription factor-DNA binding: beyond binding site motifs. , 2017, Current opinion in genetics & development.

[12]  T. Decker,et al.  Canonical and Non-Canonical Aspects of JAK–STAT Signaling: Lessons from Interferons for Cytokine Responses , 2017, Front. Immunol..

[13]  G. Natoli,et al.  Specificity and Function of IRF Family Transcription Factors: Insights from Genomics , 2016 .

[14]  O. Stegle,et al.  Deep learning for computational biology , 2016, Molecular systems biology.

[15]  M. Hofer,et al.  The emerging role of interferon regulatory factor 9 in the antiviral host response and beyond. , 2016, Cytokine & growth factor reviews.

[16]  Brandon J Thomas,et al.  A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation , 2016, Cell.

[17]  Chun Jimmie Ye,et al.  Parsing the Interferon Transcriptional Network and Its Disease Associations , 2016, Cell.

[18]  C. Glass,et al.  Molecular control of activation and priming in macrophages , 2015, Nature Immunology.

[19]  M. Hersch,et al.  TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State , 2015, The Journal of Immunology.

[20]  G. Stark,et al.  Cooperative Transcriptional Activation of Antimicrobial Genes by STAT and NF-κB Pathways by Concerted Recruitment of the Mediator Complex , 2015, Cell reports.

[21]  Andrew C. Nelson,et al.  Blimp1/Prdm1 Functions in Opposition to Irf1 to Maintain Neonatal Tolerance during Postnatal Intestinal Maturation , 2015, PLoS genetics.

[22]  A. Hoffmann,et al.  Limited specificity of IRF3 and ISGF3 in the transcriptional innate‐immune response to double‐stranded RNA , 2015, Journal of leukocyte biology.

[23]  Sijia Huang,et al.  Using epigenomics data to predict gene expression in lung cancer , 2015, BMC Bioinformatics.

[24]  G. Natoli,et al.  A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages , 2015, Genes & development.

[25]  Hongliang Li,et al.  Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. , 2015, Biochimica et biophysica acta.

[26]  Howard Y. Chang,et al.  ATAC‐seq: A Method for Assaying Chromatin Accessibility Genome‐Wide , 2015, Current protocols in molecular biology.

[27]  J. Ragoussis,et al.  IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages , 2014, Cell reports.

[28]  R. Evans,et al.  The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages , 2014, Genes & development.

[29]  G. Natoli,et al.  Chromatin contributions to the regulation of innate immunity. , 2014, Annual review of immunology.

[30]  L. Ivashkiv,et al.  Regulation of type I interferon responses , 2013, Nature Reviews Immunology.

[31]  C. Horvath,et al.  Extensive cooperation of immune master regulators IRF3 and NFκB in RNA Pol II recruitment and pause release in human innate antiviral transcription. , 2013, Cell reports.

[32]  J. Stender,et al.  Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. , 2013, Molecular cell.

[33]  P. Tewary,et al.  IRF‐5 and NF‐κB p50 co‐regulate IFN‐β and IL‐6 expression in TLR9‐stimulated human plasmacytoid dendritic cells , 2013, European journal of immunology.

[34]  Gabrielle T. Belz,et al.  Transcriptional programming of the dendritic cell network , 2013, Nature Reviews Immunology.

[35]  G. Natoli,et al.  Latent Enhancers Activated by Stimulation in Differentiated Cells , 2013, Cell.

[36]  Petra C. Schwalie,et al.  Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. , 2013, Molecular cell.

[37]  S. Rutz,et al.  A Genomic Regulatory Element That Directs Assembly and Function of Immune-Specific AP-1–IRF Complexes , 2012, Science.

[38]  Richard Bonneau,et al.  A Validated Regulatory Network for Th17 Cell Specification , 2012, Cell.

[39]  Lu Wang,et al.  BATF-JUN is critical for IRF4-mediated transcription in T cells , 2012, Nature.

[40]  Michael S. Behnke,et al.  Compensatory dendritic cell development mediated by BATF-IRF interactions , 2012, Nature.

[41]  M. Mann,et al.  Novel Murine Dendritic Cell Lines: A Powerful Auxiliary Tool for Dendritic Cell Research , 2012, Front. Immun..

[42]  Marc D. Perry,et al.  ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia , 2012, Genome research.

[43]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[44]  S. Mandrup,et al.  Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor γ in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression , 2012, Molecular and Cellular Biology.

[45]  A. Aderem,et al.  Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses , 2012, Nature Immunology.

[46]  J. MacMicking.  Interferon-inducible effector mechanisms in cell-autonomous immunity , 2012, Nature Reviews Immunology.

[47]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration , 2012, Briefings Bioinform..

[48]  C. Rice,et al.  Interferon-stimulated genes and their antiviral effector functions , 2011, Current Opinion in Virology.

[49]  J. Ragoussis,et al.  Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-κB family DNA binding , 2011, Nature Immunology.

[50]  Endre Barta,et al.  Command line analysis of ChIP-seq results , 2011 .

[51]  H. Lockstone,et al.  IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses , 2011, Nature Immunology.

[52]  J. Dixon,et al.  Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. , 2010, Genes & development.

[53]  G. Kochs,et al.  Transcription Factor Redundancy Ensures Induction of the Antiviral State* , 2010, The Journal of Biological Chemistry.

[54]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[55]  K. Honda,et al.  Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus , 2010, Proceedings of the National Academy of Sciences.

[56]  S. Smale.  Selective Transcription in Response to an Inflammatory Stimulus , 2010, Cell.

[57]  T. Taniguchi,et al.  Regulation of immunity and oncogenesis by the IRF transcription factor family , 2010, Cancer Immunology, Immunotherapy.

[58]  A. Hoffmann,et al.  A Unifying Model for the Selective Regulation of Inducible Transcription by CpG Islands and Nucleosome Remodeling , 2009, Cell.

[59]  Daniel E. Newburger,et al.  Diversity and Complexity in DNA Recognition by Transcription Factors , 2009, Science.

[60]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[61]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[62]  T. Taniguchi,et al.  The IRF family transcription factors in immunity and oncogenesis. , 2008, Annual review of immunology.

[63]  S. Harrison,et al.  An Atomic Model of the Interferon-β Enhanceosome , 2007, Cell.

[64]  K. Honda,et al.  Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression , 2007, Proceedings of the National Academy of Sciences.

[65]  K. Honda,et al.  IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors , 2006, Nature Reviews Immunology.

[66]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[67]  M. Ko,et al.  Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. , 2005, Blood.

[68]  Tak W. Mak,et al.  Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors , 2005, Nature.

[69]  David Baltimore,et al.  One Nucleotide in a κB Site Can Determine Cofactor Specificity for NF-κB Dimers , 2004, Cell.

[70]  E. Wagner,et al.  AP-1: a double-edged sword in tumorigenesis , 2003, Nature Reviews Cancer.

[71]  Govinda Rao,et al.  IRF3 mediates a TLR3/TLR4-specific antiviral gene program. , 2002, Immunity.

[72]  H. Hauser,et al.  IFN-Stimulated Gene 15 Is Synergistically Activated Through Interactions Between the Myelocyte/Lymphocyte-Specific Transcription Factors, PU.1, IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein, and IFN Regulatory Factor-4: Characterization of a New Subtype of IFN-Stimulated Response El , 2002, The Journal of Immunology.

[73]  T. Taniguchi,et al.  Gene induction pathways mediated by distinct IRFs during viral infection. , 2001, Biochemical and biophysical research communications.

[74]  C. Horvath,et al.  STAT proteins and transcriptional responses to extracellular signals. , 2000, Trends in biochemical sciences.

[75]  T. Taniguchi,et al.  Crystal structure of an IRF‐DNA complex reveals novel DNA recognition and cooperative binding to a tandem repeat of core sequences , 1999, The EMBO journal.

[76]  A. Brass,et al.  Assembly requirements of PU.1–Pip (IRF‐4) activator complexes: inhibiting function in vivo using fused dimers , 1999, The EMBO journal.

[77]  T. Decker,et al.  GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. , 1997, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[78]  U. Storb,et al.  Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator. , 1995, Genes & development.

[79]  T. Taniguchi,et al.  Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system , 1993, Molecular and cellular biology.

[80]  D. Levy,et al.  Two domains of ISGF3 gamma that mediate protein-DNA and protein-protein interactions during transcription factor assembly contribute to DNA-binding specificity , 1993, Molecular and cellular biology.

[81]  J. Darnell,et al.  ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[82]  J E Darnell,et al.  Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. , 1988, Genes & development.