title: ThPOK represses CXXC5, which induces methylation of histone H3 lysine 9 in Cd40lg promoter by association with SUV39H1: implications in repression of CD40L expression in CD8+ cytotoxic T cells.
abstract: CD40 ligand is induced in CD4(+) Th cells upon TCR stimulation and provides an activating signal to B cells, making CD40 ligand an important molecule for Th cell function. However, the detailed molecular mechanisms, whereby CD40 ligand becomes expressed on the cell surface in T cells remain unclear. Here, we showed that CD40 ligand expression in CD8(+) cytotoxic T cells was suppressed by combined epigenetic regulations in the promoter region of the Cd40lg gene, such as the methylation of CpG dinucleotides, histone H3 lysine 9, histone H3 lysine 27, and histone H4 lysine 20. As the transcription factor Th-inducing pox virus and zinc finger/Kruppel-like factor (encoded by the Zbtb7b gene) is critical in Th cell development, we focused on the role of Th-inducing pox virus and zinc finger/Kruppel-like factor in CD40 ligand expression. We found that CD40 ligand expression is moderately induced by retroviral Thpok transduction into CD8(+) cytotoxic T cells, which was accompanied by a reduction of histone H3 lysine 9 methylation and histone H3 lysine 27 methylation in the promoter region of the Cd40lg gene. Th-inducing pox virus and zinc finger/Kruppel-like factor directly inhibited the expression of murine CXXC5, a CXXC-type zinc finger protein that induced histone H3 lysine 9 methylation, in part, through an interaction with the histone-lysine N-methyltransferase SUV39H1. In addition, to inhibit CD40 ligand induction in activated CD4(+) T cells by the CXXC5 transgene, our findings indicate that CXXC5 was one of the key molecules contributing to repressing CD40 ligand expression in CD8(+) cytotoxic T cells.
authors.affiliation: Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan;
authors.forename: Yukako
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and.
authors.forename: Taku
authors.initials: T
authors.lastname: Naito
authors.affiliation: Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and.
authors.forename: Mari
authors.initials: M
authors.lastname: Tenno
authors.affiliation: Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan;
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Maruyama
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
authors.affiliation: Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; ynaoe@ncgg.go.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Naoe
mesh_terms: D000107:Acetylation; D000818:Animals; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008239:Lysine / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D023201:CD40 Ligand; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine; D008780:Methyltransferases; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C499839:CD40Ig protein, recombinant; C000601091:CXXC5 protein, mouse; C497211:Zbtb7b protein, mouse; C498700:Suv39h1 protein, mouse
keywords: CpG DNA methylation; NFAT1; epigenetic regulation; gene expression