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

Sepulveda, H.; Li, X.; Yue, X.; Angel, J. C.; Arteaga-Vazquez, L. J.; Brown, C.; Brunelli, M.; Jansz, N.; Puddu, F.; Scotcher, J.; Creed, P.; Kennedy, P. H.; Manriquez, C.; Myers, S. A.; Crawford, R.; Faulkner, G. J.; Rao, A.

doi:10.1101/2024.01.31.578097

bioRxiv · 10.1101/2024.01.31.578097

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

Sepulveda, H.·Li, X.·Yue, X.·Angel, J. C.·Arteaga-Vazquez, L. J.·Brown, C.·Brunelli, M.·Jansz, N.·Puddu, F.·Scotcher, J.·Creed, P.·Kennedy, P. H.·Manriquez, C.·Myers, S. A.·Crawford, R.·Faulkner, G. J.·Rao, A.

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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 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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Sepulveda, H., Li, X., Yue, X., Angel, J. C., Arteaga-Vazquez, L. J., Brown, C., Brunelli, M., Jansz, N., Puddu, F., Scotcher, J., Creed, P., Kennedy, P. H., Manriquez, C., Myers, S. A., Crawford, R., Faulkner, G. J., Rao, A.. 2024-01-31. OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide. https://doi.org/10.1101/2024.01.31.578097

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