| First Author | Thomas RM | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 27 | Pages | 22900-9 |
| PubMed ID | 22584578 | Mgi Jnum | J:188373 |
| Mgi Id | MGI:5440384 | Doi | 10.1074/jbc.M111.312785 |
| Citation | Thomas RM, et al. (2012) De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem 287(27):22900-9 |
| abstractText | Naive 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 ifngamma promoter is hypomethylated in naive T cells, but Th2, Th17, and iTreg differentiation is accompanied by substantial de novo DNA methylation at this locus. To determine whether de novo DNA methylation is required to restrict T helper 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 ifngamma promoter. This was accompanied by an increase in the transcriptionally permissive trimethyl H3K4 mark, and a reduction in inhibitory H3K27 methylation at the ifngamma locus. Failed de novo methylation resulted in failed silencing of the ifngamma gene, as DNMT3a-deficient Th2, Th17, and iTreg cells produced significant levels of IFNgamma 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 ifngamma gene. |
