Inhibition of DNMT1 methyltransferase activity via glucose-regulatedO-GlcNAcylation alters the epigenome

Abstract

The production of O-GlcNAc for protein O-GlcNAcylation is highly tuned to the metabolic state of the cell and thus can serve as a nutrient sensor responding to changes in metabolic pathways. We report here that excess glucose leads to increased O-GlcNAcylation of DNMT1, resulting in inhibition of DNA methyltransferase 1 (DNMT1) function and alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on DNMT1. Functional studies reveal that O-GlcNAcylation of DNMT1-S878 reduces its DNA methyltransferase activity. Treatment of cells with prolonged high glucose induces loss of DNA methylation, preferentially at partially methylated domains (PMDs). We further find that the high glucose-induced DNA methylation loss is attenuated in cells expressing DNMT1-S878A. These results establish O-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.

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide

“…OGT suppresses TET activity in mESC (this study), but TET proteins may potentiate OGT activity based on a reported ∼40% decrease in global O -GlcNAc levels in Tet2-deficient compared to control bone marrow [24]. OGT requires DNMT1 to bind KAP1 and maintain TE suppression [33], but Ogt deletion resulted in decreased levels of DNMT1/UHRF1 (this study), and DNMT1 catalytic activity was reduced in HepG2 cells cultured in high glucose and the OGA inhibitor Thiamet-G [87]. It will be important in future investigations to determine if different O -GlcNAc modifications on TET1, TET2 and DNMT1 make distinct contributions to protein stability and function.…”