Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells.
How T cells regulate interleukin 4 (IL-4) expression is not completely understood. We show here that single-positive thymocytes express IL-4, but attenuate GATA-3 expression, recruit DNA methyltransferases (Dnmts) to the Il4-Il13 locus and downregulate IL-4 expression as they mature into T cells. Type 2 polarization blocks Dnmt1 recruitment, enhances histone H3 Lys4 methylation (indicative of accessible chromatin) and initiates DNA demethylation of the locus. Dnmt1-/- CD4 and CD8 T cells derepress IL-4 expression considerably, demethylate DNA and increase H3 Lys4 methylation without affecting GATA-3 expression, demonstrating that Dnmt1 and DNA methylation are essential for proper Il4 regulation. These results indicate that Dnmts, DNA and histone methylation, and transcription factors 'collaborate' to determine appropriate Il4 expression patterns.
Department of Immunology, University of Washington, Seattle, Washington 98195, USA.
Karen W
KW
Makar
Mercedes
M
Pérez-Melgosa
Maria
M
Shnyreva
William M
WM
Weaver
David R
DR
Fitzpatrick
Christopher B
CB
Wilson
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050990:GATA3 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D007107:Immune System / Q000254:growth & development; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D015254:DNA Modification Methylases