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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE247534 | GEO | 2025/01/26

REPOSITORIES: GEO

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

Project description:The O-GlcNAc transferase OGT interacts robustly with all three mammalian TET methylcytosine dioxygenases. We show here that deletion of theOgtgene 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 engineered to abolish the TET1-OGT interaction likewise displayed a genome-wide decrease of 5mC. DNA hypomethylation in OGT-deficient cells was accompanied by de-repression of transposable elements (TEs) predominantly located in heterochromatin, and this increase in TE expression was sometimes accompanied by increased cis-expression of genes and exons located 3’ of the expressed TE. Thus, the TET-OGT interaction prevents DNA demethylation and TE expression in heterochromatin by restraining TET activity genome-wide. We suggest that OGT protects the genome against DNA hypomethylation and impaired heterochromatin integrity, preventing the aberrant increase in TE expression observed in cancer, autoimmune-inflammatory diseases, cellular senescence and ageing.

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