Abstract
The methylcytosine dioxygenases TET proteins (TET1, TET2, and TET3) play important regulatory roles in neural function. In this study, we investigated the role of TET proteins in neuronal differentiation using Neuro2a cells as a model. We observed that knockdown of TET1, TET2 or TET3 promoted neuronal differentiation of Neuro2a cells, and their overexpression inhibited VPA (valproic acid)-induced neuronal differentiation, suggesting all three TET proteins negatively regulate neuronal differentiation of Neuro2a cells. Interestingly, the inducing activity of TET protein is independent of its enzymatic activity. Our previous studies have demonstrated that srGAP3 can negatively regulate neuronal differentiation of Neuro2a cells. Furthermore, we revealed that TET1 could positively regulate srGAP3 expression independent of its catalytic activity, and srGAP3 is required for TET-mediated neuronal differentiation of Neuro2a cells. The results presented here may facilitate better understanding of the role of TET proteins in neuronal differentiation, and provide a possible therapy target for neuroblastoma.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0267-4) contains supplementary material, which is available to authorized users.
Highlights
DNA methylation at the 5-position of cytosine (5-methylcytosine, 5mC) is an important epigenetic mark involved in regulation of gene expression
class III β-Tubulin (TuJ1) was used as a neuronal differentiation marker to indicate the differentiation stages (Fig. 1D). quantitative RT-PCR (qRT-PCR) indicated that the expression levels of TET1 and TET2 but not TET3 were remarkably increased after VPA stimulation for 24 h (Fig. 1E–G)
Accumulating evidence indicates that TET proteins regulate neuronal activity-related gene expression, neuronal survival, neural development, and memory formation (Zhang et al, 2013; Kaas et al, 2013; Rudenko et al, 2013)
Summary
DNA methylation at the 5-position of cytosine (5-methylcytosine, 5mC) is an important epigenetic mark involved in regulation of gene expression. Ten-eleven translocation proteins (TET1, TET2, and TET3) are a family of Fe (II) and α-ketoglutarate-dependent dioxygenases that are capable of oxidizing 5mC to 5-hydroxymethylcytosine (5hmC) and further to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (Pastor et al, 2013; Ito et al, 2011). TET family proteins share highly homologous protein structural features. The TET family members were identified to possess a catalytic enzymatic activity conversion 5mC to 5hmC in 2009 (Tahiliani et al, 2009). TET proteins had been proved to be critical for numerous biological processes such as embryonic development, stem cell differentiation, immune regulation, and cancer formation (Tan and Shi, 2012; Xu et al, 2012; Li et al, 2015; Zhang et al, 2015; Dawlaty et al, 2013; Cimmino et al, 2015; Neri et al, 2015; Scourzic et al, 2015). 5hmC was first to identify highly enriched in VPA (Magnified) TET3 (Magnified) TET2 (Magnified) TET1
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