Inhibition of IFN-γ transcription by site-specific methylation during T helper cell development

被引:158
作者
Jones, Brendan
Chen, Jianzhu
机构
[1] MIT, Ctr Canc Res, Cambridge, MA 02139 USA
[2] MIT, Dept Biol, Cambridge, MA 02139 USA
关键词
factor binding; IFN-gamma promoter; methylation T helper cells; transcription;
D O I
10.1038/sj.emboj.7601148
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Polarization of naive CD4T cells into T helper type 2 (T(H)2) cells is characterized by expression of IL-4 and silencing of IFN-gamma. Here we show that during TH2 polarization, the DNA methyltransferase Dnmt3a is recruited to the IFN-gamma promoter and correspondingly the promoter undergoes progressive de novo methylation. Notably, the CpG located at the -53 position becomes methylated rapidly and this methylation inhibits ATF2/c-Jun and CREB transcription factor binding in vitro. In vivo, the same factors bind to the unmethylated IFN-gamma promoter in T helper type 1 (T(H)1) cells but not the methylated IFN-gamma promoter in TH2 cells. Furthermore, methylation at the -53 CpG alone is sufficient to inhibit the IFN-gamma promoter-driven reporter gene expression in a TH1 cell line. These findings suggest that rapid methylation of the evolutionarily conserved -53 CpG by Dnmt3a may suppress IFN-gamma transcription in developing TH2 cells by directly inhibiting transcription factor binding.
引用
收藏
页码:2443 / 2452
页数:10
相关论文
共 36 条
  • [1] T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells
    Afkarian, M
    Sedy, JR
    Yang, J
    Jacobson, NG
    Cereb, N
    Yang, SY
    Murphy, TL
    Murphy, KM
    [J]. NATURE IMMUNOLOGY, 2002, 3 (06) : 549 - 557
  • [2] Differential transcription directed by discrete gamma interferon promoter elements in naive and memory (effector) CD4 T cells and CD8 T cells
    Aune, TM
    Penix, LA
    Rincon, MR
    Flavell, RA
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (01) : 199 - 208
  • [3] TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes
    Avni, O
    Lee, D
    Macian, F
    Szabo, SJ
    Glimcher, LH
    Rao, A
    [J]. NATURE IMMUNOLOGY, 2002, 3 (07) : 643 - 651
  • [4] CLONING AND SEQUENCING OF A CDNA-ENCODING DNA METHYLTRANSFERASE OF MOUSE CELLS - THE CARBOXYL-TERMINAL DOMAIN OF THE MAMMALIAN ENZYMES IS RELATED TO BACTERIAL RESTRICTION METHYLTRANSFERASES
    BESTOR, T
    LAUDANO, A
    MATTALIANO, R
    INGRAM, V
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1988, 203 (04) : 971 - 983
  • [5] ACTIVATION OF MAMMALIAN DNA METHYLTRANSFERASE BY CLEAVAGE OF A ZN BINDING REGULATORY DOMAIN
    BESTOR, TH
    [J]. EMBO JOURNAL, 1992, 11 (07) : 2611 - 2617
  • [6] NEGATIVE TRANSCRIPTIONAL REGULATION OF THE INTERFERON-GAMMA PROMOTER BY GLUCOCORTICOIDS AND DOMINANT-NEGATIVE MUTANTS OF C-JUN
    CIPPITELLI, M
    SICA, A
    VIGGIANO, V
    YE, JP
    GHOSH, P
    BIRRER, MJ
    YOUNG, HA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (21) : 12548 - 12556
  • [7] Site-specific DNA methylation contributes to neurotensin/neuromedin N expression in colon cancers
    Dong, ZZ
    Wang, XF
    Evers, BM
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2000, 279 (06): : G1139 - G1147
  • [8] Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression
    Fujimoto, M
    Kitazawa, R
    Maeda, S
    Kitazawa, S
    [J]. ONCOGENE, 2005, 24 (32) : 5108 - 5118
  • [9] Gene expression in antigen-specific CD8+ T cells during viral infection
    Grayson, JM
    Murali-Krishna, K
    Altman, JD
    Ahmed, R
    [J]. JOURNAL OF IMMUNOLOGY, 2001, 166 (02) : 795 - 799
  • [10] Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets
    Grogan, JL
    Mohrs, M
    Harmon, B
    Lacy, DA
    Sedat, JW
    Locksley, RM
    [J]. IMMUNITY, 2001, 14 (03) : 205 - 215