TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn
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PROVIDER: PRJNA525449 | ENA |
REPOSITORIES: ENA
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Project description:Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.
2019-04-23 | GSE127815 | GEO
Project description:Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.
| S-EPMC6461695 | biostudies-literature
Project description:The methylcytosine dioxygenase Tet3 is highly expressed as a specific isoform in oocytes and zygotes but essentially absent from later stages of mouse preimplantation development. Here, we show that Tet3 expression promotes transdifferentiation of embryonic stem cells to trophoblast-like stem cells. By genome-wide analyses we demonstrate that TET3 associates with and co-occupies chromatin with RNA Polymerase II. Tet3 expression induces a global increase of transcription and total RNA levels, and its presence further enhances chromatin accessibility in regions open for transcription. This novel function of TET3 is not specific to the oocyte isoform, independent of its catalytic activity, the CXXC domain, or its interaction with OGT, and is localised in its highly conserved exon 4. We propose a more general role for TET3 promoting open chromatin and enhancing global transcription during changes of cellular identity, separate from its catalytic function.
2018-05-31 | GSE94688 | GEO
Project description:In this study: (1) we distinguished Tet3 target genes that are regulated by its catalytic vs. noncatalytic functions in neuroectoderm (NE) cells by transcriptomic profiling of Tet3 wildtype (WT), Tet3 catalytic mutant (Mut), and Tet3 knockout (KO) NE cells by RNA-seq. (2) We mapped genome-wide DNA methylation of Tet3-WT, Tet3-Mut, and Tet3-KO NE cells by WGBS. (3) We determined Tet3 genome-wide occupancy in Tet3-WT NE cells by CUT&Tag. (4) We mapped 5hmC rich regions in Tet3-WT, Tet3-Mut, and Tet3-KO NE cells by hmeDIP. (5) We overexpressed (OE) the Tet3 target gene Dnmt1 (D) or an empty vector (EV) in Tet3-WT, Tet3-Mut, and Tet3-KO NE cells and assessed gene expression by RNA-seq. (6) We overexpressed (OE) Tet3 (T) or an empty vector (EV) in Tet3-WT, Tet3-Mut, and Tet3-KO NE cells and examined gene expression changes in these cells by RNA-seq.
2024-04-02 | GSE237800 | GEO
Project description:Ten-eleven translocation (Tet) hydroxylases (Tet1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling Tet activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal Tet3 isoform lacking a DNA binding domain is targeted to the DNA. To identify factors binding to Tet3 we screened for proteins that co-precipitate with Tet3 from mouse retina and identified the transcriptional repressor Rest as a highly enriched Tet3-specific interactor. Rest was able to enhance Tet3 hydroxylase activity after co-expression and overexpression of Tet3 activated transcription of Rest-target genes. Moreover, we found that Tet3 also interacts with Nsd3 and two other H3K36 methyltransferases and is able to induce H3K36 trimethylation. We propose a mechanism for transcriptional activation in neurons that involves Rest-guided targeting of Tet3 to the DNA for directed 5hmC-generation and Nsd3-mediated H3K36 trimethylation.
2015-04-02 | PXD001857 | Pride
Project description:Tet3 is an Fe2+-dependent enzyme that oxidizes genomic 5-methylcytosine to 5-hydroxymethylcytosine with the help of alpha-ketoglutarate and oxygen. It is the most abundant Tet enzyme in differentiated tissues including brain. Adult brain contains the highest 5-hydroxymethylcytosine levels. How alpha-ketoglutarate is made available for the oxidation of mC in brain cells and how the Tet activity is linked to neural activity are unsolved questions. Our experiments with full mouse brains show that Tet3 interacts in the nucleus directly with selected enzymes of the mitochondrial citric acid cycle. This leads to the formation of isocitrate. Tet3 also interacts with aspartate aminotransferase, which produces oxaloacetate. Although oxaloacetate and isocitrate are biosynthetic alpha-ketoglutarate precursors, they function as inhibitors of Tet3 and are needed to protect the reactive Fe2+ center from degrading DNA. The supply of Tet3 with alpha-ketoglutarate is established by a direct interaction of Tet3 with glutamate dehydrogenase (Glud1), which converts the neurotransmitter glutamate directly into alpha-ketoglutarate. This links Tet3 function to neural activity.
2021-05-10 | PXD004518 | Pride
Project description: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 show that Tet3 is highly upregulated during neuronal differentiation and necessary to maintain silencing of pluripotency-associated genes in neural precursor cells (NPCs). Indeed, Tet3 knockdown (KD) in NPCs led to a significant increase in Oct4 and Nanog gene expression, with OCT4-positive cells appearing as cellular aggregates. Moreover, Tet3 KD led to a genome-scale loss of DNA methylation and hypermethylation of a small number of CpGs that are notably located at neurogenesis-related genes and at imprinting control regions (ICRs) of three imprinted genes (Peg10, Zrsr1 and Mcts2). Our results suggest that TET3 plays a pivotal role in maintaining neural stem cell identity and DNA methylation levels in neural precursor cells, and point to a non-catalytic role for TET3 in neural differentiation.
2019-09-23 | GSE123110 | GEO
Project description:Counter to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The causal role of active DNA demethylation in neurons, however, is not known. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair pathway. Here, we show that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of base-excision repair in hippocampal neurons elevates excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreases it. Furthermore, dysregulation of Tet3 signalling prevents homeostatic synaptic plasticity. Mechanistically, Tet3 dictates neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate basic properties and meta-plasticity of neurons via active DNA demethylation.
2015-03-25 | GSE67245 | GEO
Project description:PGC7 is a primordial germ cell (PGCs)-specific protein involved in epigenetic chromatin reprogramming in the zygote following fertilization. TET3 is a dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization. PGC7 participates in protection of DNA methylation in the maternal pronucleus by preventing conversion of 5mC to 5hmC by TET3 oxidization subsequent DNA demethylation. Thus we tested the co-localization of PGC7 and TET3 in specific loci by ChIP-seq assays.
2014-01-04 | E-GEOD-53809 | biostudies-arrayexpress
Project description:Primitive neural stem cells (NSCs) could be derived from pluripotent mouse embryonic stem (ES) cells, and then differentiate into definitive-type neural stem cells which resemble NSCs obtained from the central nervous system. Hence, primitive NSCs define an early stage of neural induction and provide a model to understand the mechanism that controls initial neural commitment. In this study, we performed microarray assay to analyze the global transcriptional profiles in mouse ES cell-derived primitive and definitive NSCs and to depict the molecular changes during the multi-staged neural differentiation process. Primitive NSCs derived directly from ESCs in Lif (p-NSC_L), primitive NSCs that were sub-cultured in the presence of Lif and FGF (p-NSC_LF), as well as definitive NSCs derived from primitive NSCs in medium containing FGF and EGF, were collected for RNA extraction and hybridization on Affymetrix microarrays. Mouse ESCs and NSCs obtained from mouse embryonic brain (E11.5) were included for controls. For each cell type, we collected two biological replicate samples for microarray analysis.
2014-03-01 | E-GEOD-44608 | biostudies-arrayexpress