Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis

Xuekun Li,Qing Dai,Yujing Li,Li Chen,Wei Zhang,Mengli Wang,Zhaohui Qin,Liping Li,Mingjiang Xu,Yunhee Kang,Bing Yao,Li Lin,Zhiqin Wang,Hao Wu,Ying Cheng,Chuan He,Peng Jin,Qiang Shu,Feng Pan

doi:10.1038/ncomms15903

Abstract

Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; however, the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Ten–eleven translocation (Tet) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and its downstream derivatives. Here we show that 5hmC is elevated during the differentiation of adult neural stem cells (aNSCs), and Tet2 is primarily responsible for modulating 5hmC dynamics. Depletion of Tet2 leads to increased aNSC proliferation and reduced differentiation in vitro and in vivo. Genome-wide transcriptional analyses reveal important epigenetic roles of Tet2 in maintaining the transcriptome landscape related to neurogenesis. Mechanistically, transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet2 and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis.

Highlights

Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored
To identify the potential transcription factor(s) that could be involved in Tet2-mediated epigenetic modulation in neurogenesis, we examined the published ChIP-seq datasets of multiple transcription factors that have been linked to neurogenesis previously, and overlapped them with the 5hmC dynamic regions regulated by Ten–eleven translocation (Tet)[2]
Our data presented here highlight the unique function of Tet[2] in dynamic 5hmC regulation during adult neurogenesis

Summary

Introduction

Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet[2] and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis. Emerging evidence suggests that various epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNAs, as well as cross-talk among these mechanisms, play important roles in fine-tuning and coordinating gene expression during adult neurogenesis[15]. Genome-wide transcriptional analyses echoed the phenotypic observations at the molecular level that the loss of Tet[2] results in significant alteration of the transcriptome landscape related to aNSC proliferation and differentiation. These data together establish an important epigenetic role for the Tet2-Foxo3a axis in adult neurogenesis

Methods

Results

Conclusion