Unexpected effects of a heterozygous Dnmt1 null mutation on age-dependent DNA hypomethylation and autoimmunity

DNA methylation modifies gene expression. Methylation patterns are establis hed during ontogeny, but they change with aging, usually with a net decreas e in methylation. The significance of this change in T cells is unknown, bu t it could contribute to autoimmunity, senescence, or both. We examined the effects of a null mutation in DNA methyltransferase 1 (Dnmt 1), a gene mai ntaining DNA methylation patterns, on immune aging. Whereas aged control mi ce developed hypomethylated DNA, autoimmunity, and signs of immune senescen ce as predicted, the knockout mice surprisingly increased DNA methylation a nd developed signs of autoimmunity and senescence more slowly. To identify potential mechanisms, we compared transcripts of DNA methyltransferase and methylcytosine binding protein family members in control and knockout mice. MeCP2, a methylcytosine binding protein involved in gene suppression and c hromatin inactivation, was the only transcript differentially expressed bet ween old knockout mice and controls, and thus it is a candidate for a gene product mediating these effects.