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Ten-Eleven Translocation 2 regulates adult neurogenesis through modulating 5mC oxidation dynamics at distinct regulatory elements

ABSTRACT: Emerging evidence suggests that various epigenetic mechanisms play important roles in regulating adult neurogenesis. Ten-Eleven Translocation (Tet) proteins, the 5mC dioxygenases, could convert 5mC stepwise to 5-hydroxymethylcytosine (5hmC) and its further oxidation products, which constitute active DNA demethylation pathway. Here we show that unlike embryonic stem cells, 5hmC is acquired upon differentiation of adult neural stem cells (NSCs). The loss of Tet2 in proliferating NSCs significantly decreases their 5hmC abundance and partially blocks the acquisition of 5hmC upon differentiation, leading to the increased proliferation and reduced differentiation both in vitro and in vivo. This impaired neurogenesis process results in a defect of learning and memory as well as depressive behavior in Tet2-/- animals. Biochemical and epigenomic analyses reveal that transcription factor Forkhead box O3 (Foxo3a) physically interacts with Tet2 and orchestrates with various forms cytosine modifications to regulate different cohorts of gene expression through distinct mechanisms. These data together establish a novel and fundamental role of Tet2 in neurogenesis by coordinating with Foxo3a to epigenetically regulate the expression of key genes involved in neurogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE65994 | GEO | 2017/07/03

SECONDARY ACCESSION(S): PRJNA275651

REPOSITORIES: GEO

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Project description:Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytsosine (5fC), and 5-carboxylcytosine (5caC). 5fC/5caC can be excised and repaired by the base excision repair (BER) pathway, implicating 5mC oxidation in active DNA demethylation. Genome-wide DNA methylation is erased in the transition from metastable states to ground state of embryonic stem cells (ESCs) and in migrating primordial germ cells (PGCs), while some resistant regions become demethylated only in gonadal PGCs. Understanding the mechanisms underlying global hypomethylation in naïve ESCs and developing PGCs will be useful for realizing cellular pluripotency and totipotency. In this study, we found that PRDM14, the PR-domain-containing transcriptional regulator, accelerates the TET-BER cycle, resulting in the promotion of active DNA demethylation in ESCs. Induction of PRDM14 expression rapidly removed the 5mC associated with transient elevation of 5hmC at pluripotency-associated genes, germline-specific genes, and imprinted loci but not across the entire genome, which resemble second wave of DNA demethylation in gonadal PGCs. PRDM14 physically interacts with TET1/TET2 and enhances the recruitment of TET1/TET2 at target loci. Knockdown of Tet1/Tet2 impaired transcriptional regulation and DNA demethylation by PRDM14. The repression of the BER pathway by administration of pharmacological inhibitors against APE1 and PARP1 and the knockdown of thymine DNA glycosylase (TDG) also impaired DNA demethylation by PRDM14. Furthermore, DNA demethylation induced by PRDM14 normally takes place in the presence of aphidicolin, which is an inhibitor of G1/S progression. Together, our analysis provides mechanistic insight into DNA demethylation in naive pluripotent stem cells and developing PGCs. To investigate the function of TET1/TET2 in transcriptional regulation by PRDM14 in ESCs, we exploited microarray analysis using total mRNA derived from Scramble, Scramble + PRDM14, Tet1/Tet2 KD, Tet1/Tet2 KD + PRDM14 mouse ESC.

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Ten-Eleven Translocation 2 regulates adult neurogenesis through modulating 5mC oxidation dynamics at distinct regulatory elements

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