DNA去甲基化
DNA甲基化
5-羟甲基胞嘧啶
基因敲除
生物
神经发生
细胞生物学
神经干细胞
细胞分化
表观遗传学
同源盒蛋白纳米
祖细胞
基因组印记
分子生物学
干细胞
胚胎干细胞
遗传学
诱导多能干细胞
基因
基因表达
作者
Mafalda Santiago,Cláudia Antunes,Marta Guedes,Michelina Iacovino,Michael Kyba,Wolf Reik,Nuno Sousa,Luísa Pinto,Miguel R. Branco,C. Joana Marques
标识
DOI:10.1007/s00018-019-03335-7
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI