OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide
The O-GlcNAc transferase OGT interacts robustly with all three mammalian TET methylcytosine dioxygenases. We show here that deletion of the Ogt gene in mouse embryonic stem cells (mESC) results in a widespread increase in the TET product 5-hydroxymethylcytosine (5hmC) in both euchromatic and heterochromatic compartments, with concomitant reduction of the TET substrate 5-methylcytosine (5mC) at the same genomic regions. mESC treated with an OGT inhibitor displayed increased 5hmC, and attenuating the TET1-OGT interaction in mESC resulted in a genome-wide decrease of 5mC, indicating that OGT restrains TET activity and limits untoward DNA demethylation in a manner that requires the TET-OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by de-repression of transposable elements (TEs) predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in TE expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and ageing. Overall design: To investigate the effect of knock out of the OGT gene on genome-wide distribution of methylated and hydroxymethylated cytostine bases at base resolution using 6-base sequencing