Inhibition of DNMT1 methyltransferase activity via glucose-regulated <i>O</i>-GlcNAcylation alters the epigenome.

Abstract

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by <i>O</i>-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated <i>O</i>-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is <i>O</i>-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that <i>O</i>-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish <i>O</i>-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.