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TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice.

ABSTRACT: The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na⁺/K⁺/Cl^- transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.

SUBMITTER: Moyon S

PROVIDER: S-EPMC8185117 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Project description:Adult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair. While DNA hydroxy-methylation and high levels of TET1 were detected in young adult mice during myelin regeneration after demyelination, this process was defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulated the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identified solute carrier gene families as TET1 targets. Lower transcripts for these genes in Tet1 mutants and old mice were associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish Slc12a2b mutants. We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult myelination after injury, by modulating the levels of the solute carrier SLC12A2 at the axo-myelin interface.

2020-03-14 | GSE137611 | GEO

α5 integrin regulates hepatic tight junctions through SRC-TET1-mediated DNA hydroxymethylation.

Project description:The functional tight junctions' integrity plays an important role in liver physiology. A variety of liver diseases have been associated with the perturbation of tight junctions. Herein, we showed that the lower expression of α5 integrin in hepatocytes in patients with liver cirrhosis is associated with matrix deposition in the space of Disse. Selective silencing of α5 integrin in hepatocytes compromised the ultrastructure of tight junctions by downregulating claudin 1 in an SRC (proto-oncogene, non-receptor tyrosine kinase) signaling-dependent manner. α5 integrin signaling induced SRC-TET-mediated changes in 5-hydroxymethylcytosine and 5-methylcytosine levels in hepatocytes in vitro and in vivo. hMeDIP sequencing showed intergenic hypohydroxymethylation of the claudin 1 gene in hepatocytes after α5 integrin silencing in mice. Therefore, understanding the mechanisms regulating hepatic tight junction integrity in which α5 integrin-SRC signaling and epigenetic modifications cooperate might help advance the development of useful diagnostics and therapeutic approaches for liver disease.

| S-EPMC9709229 | biostudies-literature

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Project description:TET1-mediated DNA hydroxy-methylation regulates adult remyelination

| PRJNA566002 | ENA

Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation.

Project description:Methylated cytosines are associated with gene silencing. The ten-eleven translocation (TET) hydroxylases, which oxidize methylated cytosines to 5-hydroxymethylcytosine (5hmC), are essential for cytosine demethylation. Gene silencing and activation are critical for intestinal stem cell (ISC) maintenance and differentiation, but the potential role of TET hydroxylases in these processes has not yet been examined. Here, we generated genome-wide maps of the 5hmC mark in ISCs and their differentiated progeny. Genes with high levels of hydroxymethylation in ISCs are strongly associated with Wnt signaling and developmental processes. We found Tet1 to be the most abundantly expressed Tet gene in ISCs; therefore, we analyzed intestinal development in Tet1-deficient mice and determined that these mice are growth-retarded, exhibit partial postnatal lethality, and have significantly reduced numbers of proliferative cells in the intestinal epithelium. In addition, the Tet1-deficient intestine displays reduced organoid-forming capacity. In the Tet1-deficient crypt, decreased expression of Wnt target genes such as Axin2 and Lgr5 correlates with lower 5hmC levels at their promoters. These data demonstrate that Tet1-mediated DNA hydroxymethylation plays a critical role in the epigenetic regulation of the Wnt pathway in intestinal stem and progenitor cells and consequently in the self-renewal of the intestinal epithelium.

| S-EPMC5131782 | biostudies-literature

TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.

Project description:The ten-eleven-translocation 5-methylcytosine dioxygenase (TET) family of enzymes catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), a modified cytosine base that facilitates gene expression. Cells respond to hypoxia by inducing a transcriptional program regulated in part by oxygen-dependent dioxygenases that require Fe(II) and α-ketoglutarate. Given that the TET enzymes also require these cofactors, we hypothesized that the TETs regulate the hypoxia-induced transcriptional program. Here, we demonstrate that hypoxia increases global 5-hmC levels, with accumulation of 5-hmC density at canonical hypoxia response genes. A subset of 5-hmC gains colocalize with hypoxia response elements facilitating DNA demethylation and HIF binding. Hypoxia results in transcriptional activation of TET1, and full induction of hypoxia-responsive genes and global 5-hmC increases require TET1. Finally, we show that 5-hmC increases and TET1 upregulation in hypoxia are HIF-1 dependent. These findings establish TET1-mediated 5-hmC changes as an important epigenetic component of the hypoxic response.

| S-EPMC4516227 | biostudies-literature

Ten-eleven translocation 1 mediated-DNA hydroxymethylation is required for myelination and remyelination in the mouse brain.

Project description:Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.

| S-EPMC8385008 | biostudies-literature

DSCR1-mediated TET1 splicing regulates miR-124 expression to control adult hippocampal neurogenesis

Project description:Whether epigenetic factors such as DNA methylation and microRNAs interact to control adult hippocampal neurogenesis is not fully understood. Here we show that Down syndrome critical region1 (DSCR1) protein plays a key role in adult hippocampal neurogenesis by modulating two epigenetic factors, TET1 and miR-124. We find that DSCR1 mutant mice have impaired adult hippocampal neurogenesis. DSCR1 binds to TET1 introns to regulate splicing of TET1, thereby modulating TET1 level. Furthermore, TET1 controls the demethylation of the miRNA-124 promoter to mediate miR-124 expression. Correcting the level of TET1 in DSCR1 knockout mice is sufficient to prevent defective adult neurogenesis. Importantly, restoring DSCR1 level in a Down syndrome mouse model effectively rescued adult neurogenesis and learning and memory deficits. Our study reveals that DSCR1 plays a critical upstream role in epigenetic regulation of adult neurogenesis and provides insights into potential therapeutic strategy for treating cognitive defects in Down syndrome.

| S-SCDT-EMBOJ-2018-101293 | biostudies-other

DSCR1-mediated TET1 splicing regulates miR-124 expression to control adult hippocampal neurogenesis.

Project description:Whether epigenetic factors such as DNA methylation and microRNAs interact to control adult hippocampal neurogenesis is not fully understood. Here, we show that Down syndrome critical region 1 (DSCR1) protein plays a key role in adult hippocampal neurogenesis by modulating two epigenetic factors: TET1 and miR-124. We find that DSCR1 mutant mice have impaired adult hippocampal neurogenesis. DSCR1 binds to TET1 introns to regulate splicing of TET1, thereby modulating TET1 level. Furthermore, TET1 controls the demethylation of the miRNA-124 promoter to modulate miR-124 expression. Correcting the level of TET1 in DSCR1 knockout mice is sufficient to prevent defective adult neurogenesis. Importantly, restoring DSCR1 level in a Down syndrome mouse model effectively rescued adult neurogenesis and learning and memory deficits. Our study reveals that DSCR1 plays a critical upstream role in epigenetic regulation of adult neurogenesis and provides insights into potential therapeutic strategy for treating cognitive defects in Down syndrome.

| S-EPMC6627232 | biostudies-literature

Tet1 regulates adult hippocampal neurogenesis and cognition.

Project description:DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in embryonic stem cells and neurons in mammals. However, its biological function in vivo is largely unknown. Here, we demonstrate that Tet1 plays an important role in regulating neural progenitor cell proliferation in adult mouse brain. Mice lacking Tet1 exhibit impaired hippocampal neurogenesis accompanied by poor learning and memory. In adult neural progenitor cells deficient in Tet1, a cohort of genes involved in progenitor proliferation were hypermethylated and downregulated. Our results indicate that Tet1 is positively involved in the epigenetic regulation of neural progenitor cell proliferation in the adult brain.

| S-EPMC4474382 | biostudies-literature

Tet1-mediated DNA demethylation regulates neuronal cell death induced by oxidative stress.

Project description:Epigenetic regulations including DNA methylation and demethylation play critical roles in neural development. However, whether DNA methylation and demethylation may play a role in neuronal cell death remains largely unclear. Here we report that the blockade of DNA methyltransferase inhibits apoptosis of cerebellar granule cells and cortical neurons in response to oxidative stress. We found that knockdown of ten-eleven translocation methylcytosine dioxygenase (Tet1), a critical enzyme for DNA demethylation, significantly increase apoptosis of cerebellar granule cells induced by hydrogen peroxide. Moreover, cerebellar granule cells from tet1(null) mice appeared to be more sensitive to oxidative stress, suggesting the critical role of Tet1 in neuronal cell death. We further showed that the expression of Klotho, an antiaging protein, in cerebellar granule cells is tightly regulated by DNA methylation. Finally, we found that knockdown of Klotho diminished the rescue effects of DNA methyltransferase inhibitors and Tet1 on neuronal cell death induced by oxidative stress. Our work revealed the role of Tet1-mediated DNA demethylation on neuronal protection against oxidative stress and provided the molecular mechanisms underlying the epigenetic regulation of neuronal cell death, suggesting the role of Klotho in regulating neuronal cell death in response to oxidative stress.

| S-EPMC4284502 | biostudies-literature

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