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Mol. Life Sci."],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:p>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 <jats:italic>Tet3<\/jats:italic> in neural precursor cells (NPCs), using a stable and inducible knockdown system and an in vitro neural differentiation protocol. We show that <jats:italic>Tet3<\/jats:italic> is upregulated during neural differentiation, whereas <jats:italic>Tet1<\/jats:italic> is downregulated. Surprisingly, <jats:italic>Tet3<\/jats:italic> knockdown led to a de-repression of pluripotency-associated genes such as <jats:italic>Oct4<\/jats:italic>, <jats:italic>Nanog<\/jats:italic> or <jats:italic>Tcl1<\/jats:italic>, with concomitant hypomethylation. Moreover, in <jats:italic>Tet3<\/jats:italic> knockdown NPCs, we observed the appearance of OCT4-positive cells forming cellular aggregates, suggesting de-differentiation of the cells. Notably, <jats:italic>Tet3<\/jats:italic> 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 <jats:italic>Peg10<\/jats:italic>, <jats:italic>Zrsr1<\/jats:italic> and <jats:italic>Mcts2<\/jats:italic> 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.<\/jats:p>","DOI":"10.1007\/s00018-019-03335-7","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T23:50:08Z","timestamp":1571874608000},"page":"2871-2883","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Tet3 regulates cellular identity and DNA methylation in neural progenitor cells"],"prefix":"10.1007","volume":"77","author":[{"given":"Mafalda","family":"Santiago","sequence":"first","affiliation":[]},{"given":"Claudia","family":"Antunes","sequence":"additional","affiliation":[]},{"given":"Marta","family":"Guedes","sequence":"additional","affiliation":[]},{"given":"Michelina","family":"Iacovino","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Kyba","sequence":"additional","affiliation":[]},{"given":"Wolf","family":"Reik","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Lu\u00edsa","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Miguel R.","family":"Branco","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-3773","authenticated-orcid":false,"given":"C. 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