De Novo DNA methylation is required to restrict T helper lineage plasticity

Rajan M. Thomas, Christopher J. Gamper, Brian H. Ladle, Jonathan D. Powell, Andrew D. Wells

Research output: Contribution to journalArticlepeer-review

Abstract

Naïve CD4+ T cells are highly plastic and can differentiate into discrete lineages with unique functions during an immune response. Once differentiated, helper T cells maintain a stable transcriptional memory of their initial lineage choice and resist redifferentiation. During embryogenesis, de novo DNA methylation operates on the hypomethylated genome of the blastocyst to achieve tissue-specific patterns of gene expression. Similarly, the ifnγ promoter is hypomethylated in naïve T cells, but Th2, Th17, and iTreg differentiation is accompanied by substantial de novo DNA methylation at this locus. To determine whether de novoDNAmethylation is required to restrictThelper lineage plasticity, we used mice with T cell-specific deletion of the methyltransferase DNMT3a. Induction of lineage-specific cytokines occurred normally in the absence of DNMT3a, however, DNMT3a-deficient Th2, Th17, and iTreg completely failed to methylate the ifnγ promoter. This was accompanied by an increase in the transcriptionally permissive trimethyl H3K4 mark, and a reduction in inhibitory H3K27 methylation at the ifnγ locus. Failed de novo methylation resulted in failed silencing of the ifnγ gene, as DNMT3a-deficient Th2, Th17, and iTreg cells produced significant levels of IFNγ following restimulation in the presence of IL-12. Therefore, DNMT3a-mediated DNA methylation restricts T helper plasticity by establishing an epigenetically silent chromatin structure at regulatory regions of the ifnγ gene.

Original languageEnglish (US)
Pages (from-to)22900-22909
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number27
DOIs
StatePublished - Jun 29 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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