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TET3 regulates cellular identity and DNA methylation in neural progenitor cells

ABSTRACT: TET3 regulates cellular identity and DNA methylation in neural progenitor cells

PROVIDER: PRJNA507587 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8261310.fastq.gz	Fastqsanger.gz
	SRR8261311.fastq.gz	Fastqsanger.gz
	SRR8261312.fastq.gz	Fastqsanger.gz
	SRR8261313.fastq.gz	Fastqsanger.gz
	SRR8261314.fastq.gz	Fastqsanger.gz

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TET3 regulates cellular identity and DNA methylation in neural progenitor cells

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

Tet3 regulates cellular identity and DNA methylation in neural progenitor cells.

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 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.

| S-EPMC7326798 | biostudies-literature

Redirected nuclear glutamate dehydrogenase supplies Tet3 with a-ketoglutarate in neurons

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

Single-cell transcriptomics reveals the cellular identity of a novel progenitor population crucial for murine neural tube closure

Project description:Single-cell transcriptomics reveals the cellular identity of a novel progenitor population crucial for murine neural tube closure

| PRJNA1032033 | ENA

Mina53 demethylates histone 4 arginine 3 asymmetric di-methylation to regulate neural stem/progenitor cell identity

Project description:Arginine methylation of histones plays a critical role in regulating gene expression. The writers (methyltransferases) and readers of methylarginine marks are well-known, but the erasers－arginine demethylases－remain mysterious. Here we identify Myc-induced nuclear antigen 53 (Mina53), a jumonji C domain containing protein, as an arginine demethylase for removing asymmetric di-methylation at arginine 3 of histone H4 (H4R3me2a). Using photoaffinity capture method, we first identified Mina53 as an interactor of H4R3me2a. Biochemical assays in vitro and in cells characterized the arginine demethylation activity of Mina53. Molecular dynamics simulations provide further atomic-level evidence that Mina53 acts on H4R3me2a. In a transgenic mouse model, specific Mina53 deletion in neural stem/progenitor cells prevented H4R3me2a demethylation at distinct genes clusters, dysregulating genes important for neural stem/progenitor cell proliferation and differentiation, and consequently impairing the cognitive function of mice. Collectively, we identify Mina53 as a bona fide H4R3me2a eraser, expanding the understanding of epigenetic gene regulation.

2024-10-22 | PXD045247 | Pride

Zrf1 is required to establish and maintain neural progenitor identity (mRNA array)

Project description:Our work aims to characterize the role of Zrf1 in the generation and maintenance of neural progenitor cells (NPCs) Gene expression profile of shCtrl and shZrf1 cells during generation of RGC-like NPC from ESC at day 6 of neural induction. Cells were grown according to this protocol: Bibel et al, Nat Prot., 2007

2013-12-21 | E-GEOD-53541 | biostudies-arrayexpress

Tet2 and Tet3 mediated active cytosine hydroxymethylation in Six2 progenitor cells is critical for nephron progenitor differentiation and nephron endowment

Project description:Nephron endowment is a key determinant of later life hypertension and kidney disease. Here we studied whether epigenetic changes, specifically the ten–eleven translocation (Tet) DNA demethylase family, Tet1, Tet2, and Tet3-mediated active DNA hydroxymethylation is necessary for gene expression regulation and kidney differentiation. We generated mice with deletion of Tet1, Tet2 or Tet3 in Six2 positive nephron progenitors (NP). We did not observe changes in development or kidney function in mice with nephron progenitor-specific deletion of Tet1, Tet2, Tet3 or Tet1/Tet2 or Tet1/Tet3. On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2-positive NPs resulted in defect in mesenchymal to epithelial transition and renal vesicle differentiation. Whole genome bisulfite sequencing, single cell RNA sequencing, and gene and protein expression assay identified a defect in expression in genes in the WNT-β-catenin signaling pathway in absence of Tet2 and Tet3 due to a failure in demethylation of these loci. Our results indicate the key role of Tet2 and Tet3-mediated active cytosine hydroxymethylation in NPs in kidney development and nephron endowment.

2022-11-23 | GSE212715 | GEO

Ultrasound-mediated ultra effective cellular reprogramming of human fibroblasts into neural progenitor-like cells [MBD-Seq]

Project description:We have developed an ultra effective method of triggering fast cellular reprogramming into neural progenitor cells (NPCs) with significant yields, called ultrasound-directed permeation of environmental transition-guided cellular reprogramming (Entr).

2019-09-20 | GSE87204 | GEO

Ultrasound-mediated ultra effective cellular reprogramming of human fibroblasts into neural progenitor-like cells [RNA-Seq]

2019-09-20 | GSE86644 | GEO

Regional identity of human neural stem cells determinesoncogenic responses to histone 1H3.3 mutants

Project description:Regional identity of human neural stem cells determinesoncogenic responses to histone 1H3.3 mutants

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