Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming1

STAT4 is a critical component in the development of inflammatory adaptive immune responses. It has been extensively characterized as a lineage-determining factor in Th1 development. However, the genetic program activated by STAT4 that results in an inflammatory cell type is not well defined. In this report, we use DNA isolated from STAT4-chromatin immunoprecipitation to perform chromatin immunoprecipitation-on-chip analysis of over 28,000 mouse gene promoters to identify STAT4 targets. We demonstrate that STAT4 binds multiple gene-sets that program distinct components of the Th1 lineage. Although many STAT4 target genes display STAT4-dependent IL-12-inducible expression, other genes displayed IL-12-induced histone modifications but lack induction, possibly due to high relative basal expression. In the subset of genes that STAT4 programs for expression in Th1 cells, IL-12-induced mRNA levels remain increased for a longer time than mRNA from genes that are not programmed. This suggests that STAT4 binding to target genes, while critical, is not the only determinant for STAT4-dependent gene programming during Th1 differentiation.

[1]  G. Koretzky,et al.  T cell activation. , 2009, Annual review of immunology.

[2]  A. Sher,et al.  Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii , 2008, The Journal of experimental medicine.

[3]  M. Kaplan,et al.  Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. , 2008, Immunity.

[4]  Y. Belkaid,et al.  T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance , 2008, Nature.

[5]  M. Kaplan,et al.  Transcription Factor-Dependent Chromatin Remodeling of Il18r1 during Th1 and Th2 Differentiation1 , 2008, The Journal of Immunology.

[6]  Wentian Li,et al.  STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. , 2007, The New England journal of medicine.

[7]  Allen D. Delaney,et al.  Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing , 2007, Nature Methods.

[8]  M. Kaplan,et al.  Stat4 limits DNA methyltransferase recruitment and DNA methylation of the IL‐18Rα gene during Th1 differentiation , 2007, The EMBO journal.

[9]  L. Rogge,et al.  Chromatin remodeling by the SWI/SNF‐like BAF complex and STAT4 activation synergistically induce IL‐12Rβ2 expression during human Th1 cell differentiation , 2007, The EMBO journal.

[10]  D. G. Zisoulis,et al.  T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype. , 2006, Blood.

[11]  J. O’Shea,et al.  Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. , 2006, Blood.

[12]  Fuping Zhang,et al.  T helper type 1–specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent , 2006, The Journal of experimental medicine.

[13]  T. Huang,et al.  T-bet Binding to Newly Identified Target Gene Promoters Is Cell Type-independent but Results in Variable Context-dependent Functional Effects*♦ , 2006, Journal of Biological Chemistry.

[14]  Mark Gerstein,et al.  Global changes in STAT target selection and transcription regulation upon interferon treatments. , 2005, Genes & development.

[15]  T. Aune,et al.  Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Kaplan,et al.  Impaired interferon-gamma production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma. , 2005, Blood.

[17]  Bert W O'Malley,et al.  Identification of target genes in breast cancer cells directly regulated by the SRC-3/AIB1 coactivator. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  T. Speed,et al.  GOstat: find statistically overrepresented Gene Ontologies within a group of genes. , 2004, Bioinformatics.

[19]  G. Crooks,et al.  WebLogo: a sequence logo generator. , 2004, Genome research.

[20]  R. Lahesmaa,et al.  Early Target Genes of IL-12 and STAT4 Signaling in Th Cells1 , 2004, The Journal of Immunology.

[21]  M. Kaplan,et al.  STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus* , 2004, Journal of Biological Chemistry.

[22]  L. Naeger,et al.  Distinct requirements for the naturally occurring splice forms Stat4α and Stat4β in IL‐12 responses , 2003 .

[23]  R. Salomon,et al.  Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-γ Response to Viral Infection , 2002, Science.

[24]  Chilakamarti V. Ramana,et al.  Stat1-dependent and -independent pathways in IFN-γ-dependent signaling , 2002 .

[25]  R. Flavell,et al.  GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. , 2001, Immunity.

[26]  M. Kaplan,et al.  Stat4 Regulates Multiple Components of IFN-γ-Inducing Signaling Pathways1 , 2000, The Journal of Immunology.

[27]  Jan Mous,et al.  Touching base , 2000, Nature Genetics.

[28]  S. Szabo,et al.  Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells , 1997, The Journal of experimental medicine.

[29]  T. Hoey,et al.  Cooperative DNA Binding and Sequence-Selective Recognition Conferred by the STAT Amino-Terminal Domain , 1996, Science.

[30]  K. Takase,et al.  [T cell activation]. , 1995, Ryumachi. [Rheumatism].

[31]  R. Schreiber,et al.  Interferon-γ and cancer immunoediting , 2005 .

[32]  M. Kaplan.  STAT4: a critical regulator of inflammation in vivo. , 2005, Immunologic research.

[33]  Wyeth W. Wasserman,et al.  JASPAR: an open-access database for eukaryotic transcription factor binding profiles , 2004, Nucleic Acids Res..

[34]  G. Crooks,et al.  WebLogo: A sequence logo generator, Genome Research, , 2004 .

[35]  Jianfei Yang,et al.  T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells , 2002, Nature Immunology.

[36]  John J. Wyrick,et al.  Genome-wide location and function of DNA binding proteins. , 2000, Science.

[37]  Charles Elkan,et al.  Fitting a Mixture Model By Expectation Maximization To Discover Motifs In Biopolymer , 1994, ISMB.