title: Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation.
abstract: The STAT transcription factor STAT4 is a critical regulator of Th1 differentiation and inflammatory disease. Yet, how STAT4 regulates gene expression is still unclear. In this report, we define a STAT4-dependent sequence of events including histone H3 lysine 4 methylation, Jmjd3 association with STAT4 target loci, and a Jmjd3-dependent decrease in histone H3 lysine 27 trimethylation and DNA methyltransferase (Dnmt) 3a association with STAT4 target loci. Dnmt3a has an obligate role in repressing Th1 gene expression, and in Th1 cultures deficient in both STAT4 and Dnmt3a, there is recovery in the expression of a subset of Th1 genes that is sufficient to increase IFN-γ production. Moreover, although STAT4-deficient mice are protected from the development of experimental autoimmune encephalomyelitis, mice deficient in STAT4 and conditionally deficient in Dnmt3a in T cells develop paralysis. Th1 genes that are derepressed in the absence of Dnmt3a have greater induction after the ectopic expression of the Th1-associated transcription factors T-bet and Hlx1. Together, these data demonstrate that STAT4 and Dnmt3a play opposing roles in regulating Th1 gene expression, and that one mechanism for STAT4-dependent gene programming is in establishing a derepressed genetic state susceptible to transactivation by additional fate-determining transcription factors.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Duy
authors.initials: D
authors.lastname: Pham
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Crystal C
authors.initials: CC
authors.lastname: Walline
authors.forename: Rajarajeswari
authors.initials: R
authors.lastname: Muthukrishnan
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering; D017471:Receptors, Interferon / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor
chemical_list: D002843:Chromatin; D050677:Core Binding Factor Alpha 3 Subunit; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006657:Histones; D018398:Homeodomain Proteins; D007371:Interferon-gamma; D018664:Interleukin-12; D056484:Jumonji Domain-Containing Histone Demethylases; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor; C000715535:Dnmt3a protein, mouse; C489999:Hlx protein, mouse; C493730:Runx3 protein, mouse; C494091:Stat4 protein, mouse; C523761:Kdm6b protein, mouse