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<p><i>O-</i>GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the <i>Ogt</i> gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1–OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate 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 derepression of transposable elements 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 transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月28日

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  • Hugo Sepulveda,
  • Xiang Li,
  • Leo J. Arteaga-Vazquez,
  • Isaac F. López-Moyado,
  • Melina Brunelli,
  • Lot Hernández-Espinosa,
  • Xiaojing Yue,
  • J. Carlos Angel,
  • Caitlin Brown,
  • Zhen Dong,
  • Natasha Jansz,
  • Fabio Puddu,
  • Aurélie Modat,
  • Jamie Scotcher,
  • Páidí Creed,
  • Patrick H. Kennedy,
  • Cindy Manriquez-Rodriguez,
  • Samuel A. Myers,
  • Robert Crawford,
  • Geoffrey J. Faulkner,
  • Anjana Rao

摘要

O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1–OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate 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 derepression of transposable elements 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 transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.