Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-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 O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-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 O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-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 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.

Epigenomic insights into common human disease pathology

“…However, further DMCs were still able to be identified in a recent US study in African- and European-Americans with seven novel findings in the former and three in the latter [ 227 ]. Intriguing functional insights into the long-term effects of hyperglycaemia have identified glucose increasing the post-translational modification, O-GlcNAcylation at S878, of DNMT1, inhibiting this maintenance enzyme in the liver, leading to downstream alterations of the epigenome [ 228 ].…”

Can O-GIcNAc Transferase (OGT) Complex Be Used as a Target for the Treatment of Hematological Malignancies?

“…Moreover, abnormal tumor cell metabolism may alter the O -GlcNAcylation of TET2 proteins, thereby affecting their stability. Conversely, the absence of the TET function in tumors may affect the cytosolic and/or cytoplasmic distribution of OGT, which in turn may affect the stability of tumor suppressors and oncogenes such as p53 [ 124 ] and MYC [ 125 ]. This implies that the OGT/TET complex may influence the development of hematological malignancies by regulating epigenetic modifications, including DNA methylation and histone methylation associated with the positive regulation of gene expression.…”