Tet3 regulates cellular identity and DNA methylation in neural progenitor cells

Mafalda Santiago, Claudia Antunes, Marta Guedes, Michelina Iacovino, Michael Kyba, Wolf Reik, Nuno Sousa, Luísa Pinto, Miguel R. Branco, C. Joana Marques

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

TET enzymes oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), a process thought to be intermediary in an active DNA demethylation mechanism. Notably, 5hmC is highly abundant in the brain and in neuronal cells. Here, we interrogated the function of Tet3 in neural precursor cells (NPCs), using a stable and inducible knockdown system and an in vitro neural differentiation protocol. We show that Tet3 is upregulated during neural differentiation, whereas Tet1 is downregulated. Surprisingly, Tet3 knockdown led to a de-repression of pluripotency-associated genes such as Oct4, Nanog or Tcl1, with concomitant hypomethylation. Moreover, in Tet3 knockdown NPCs, we observed the appearance of OCT4-positive cells forming cellular aggregates, suggesting de-differentiation of the cells. Notably, Tet3 KD led to a genome-scale loss of DNA methylation and hypermethylation of a smaller number of CpGs that are located at neurogenesis-related genes and at imprinting control regions (ICRs) of Peg10, Zrsr1 and Mcts2 imprinted genes. Overall, our results suggest that TET3 is necessary to maintain silencing of pluripotency genes and consequently neural stem cell identity, possibly through regulation of DNA methylation levels in neural precursor cells.

Original languageEnglish (US)
JournalCellular and Molecular Life Sciences
DOIs
StateAccepted/In press - 2019

Keywords

  • 5-hydroxymethylcytosine
  • Imprinted genes
  • Neural stem cells
  • Neurogenesis
  • Pluripotency
  • TET enzymes

PubMed: MeSH publication types

  • Journal Article

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  • Cite this

    Santiago, M., Antunes, C., Guedes, M., Iacovino, M., Kyba, M., Reik, W., Sousa, N., Pinto, L., Branco, M. R., & Marques, C. J. (Accepted/In press). Tet3 regulates cellular identity and DNA methylation in neural progenitor cells. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-019-03335-7