TET1-mediated DNA hydroxy-methylation regulates adult remyelination
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ABSTRACT:
PROVIDER: PRJNA566002 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR10134300_1.fastq.gz | Fastqsanger.gz | |||
| SRR10134300_2.fastq.gz | Fastqsanger.gz | |||
| SRR10134301_1.fastq.gz | Fastqsanger.gz | |||
| SRR10134301_2.fastq.gz | Fastqsanger.gz | |||
| SRR10134302_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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
Project description:Adult myelination is recognized as essential for brain function and response to injury and yet, its molecular understanding is mostly inferred from developmental studies. In this study, we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult, but not for developmental, myelin formation. While hydroxy-methylation and high levels of TET1 were detected in young adult mice during myelin regeneration after lysolecithin-induced demyelination, this process was defective in older mice. Lineage specific ablation of the enzyme Tet1 (but not of Tet2) recapitulated the age-related decline of TET1 and inefficient remyelination, without impacting developmental myelination. Genome-wide DNA hydroxy-methylation profiling of adult progenitors and mature oligodendrocytes, identified solute carriers regulating neuronal-glial communication as gene targets, whose expression was dramatically decreased in mutants and in older mice. We conclude that TET1-mediated hydroxy-methylation is critical for adult myelination in response to injury.
2020-03-14 | GSE122446 | GEO
Project description: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.
| S-EPMC8185117 | biostudies-literature
Project description:DNA hydroxymethylation by epigenetic modifiers TET dioxygenases is critical for gene transcription in various biological processes, however, its role in oligodendrocyte maturation and functions remain elusive. Here, we found that mice lacking Tet1 in the oligodendrocyte lineage exhibited hypomyelination in the CNS in the juvenile stage, leading to defects in action potential propagation, motor coordination, anxiety-like behavior and spatial memory capacities. Although the myelin deficiency recovered in adulthood, remyelination after cuprizone-induced demyelination was compromised in Tet1cKO mice. By integrating transcriptome and DNA methylation profiles, we identified a cohort of genes that were differentially regulated by Tet1 and hyperhydroxymethylation, including the genes associated with Ca2+ transportation. Tet1-deficient OPCs exhibited a reduction in [Ca2+] oscillations, while the agonists of calcium internal stores rescued the differentiation defect of Tet1-deficient OPCs. Thus, our results suggest that stage-specific Tet1-mediated epigenetic programming in oligodendrocytes maintain Ca2+ homeostasis for differentiation and regulate neuronal activities and myelin repair.
2019-11-20 | GSE122838 | GEO
Project description:Age-dependent decline of TET1-mediated DNA hydroxy-methylation impairs myelin regeneration after injury
| PRJNA505260 | ENA
Project description:Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here, we examined a possible role for the newly identified methylcytosine oxidase, ten eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We show that chronic social defeat stress, an ethologically validated mouse model of depression, decreased Tet1 expression in nucleus accumbens (NAc), a key brain reward region, in stress susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after Tet1 knockout and found that immune-related genes are the most highly regulated. Interestingly, many of these genes are also upregulated in NAc of resilient mice after chronic social defeat stress. Together, these findings link Tet1 to stress responses and identify novel targets for future antidepressant drug discovery efforts.
2017-09-06 | GSE76977 | GEO
Project description:The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal demyelination in the rat CNS. White matter tracts in the rat caudal cerebellar peduncles were focally demyelinated using 0.1% ethidium bromide, the lesions were isolated using laser capture microdissection at 5, 14 and 28 days postlesion, followed by RNA extraction and Illumina beadarray analysis of differentially expressed transcripts. We found transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination, and that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy. 9 Samples analysed, 3 different time points each with 3 biological replicates.
2010-10-22 | E-GEOD-24821 | biostudies-arrayexpress
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. hMeDIP-seq analysis of genomic 5-hydroxymethylcytosine in HEK293T cells overexpressing mTET1-CD, TET1-CD, mTET1-FL, or TET1-FL
2014-06-04 | E-GEOD-44036 | biostudies-arrayexpress
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. HEK293T cells were transfected with wild type or catalytically mutant TET1 expression plasmids (TET1-CD, mTET1-CD, TET1-FL and mTET1-FL), or subjected to shRNA-mediated TET1 knockdown. Total RNA samples were extracted and assayed on Affymetrix microarrays
2014-06-04 | E-GEOD-50016 | biostudies-arrayexpress
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. Genome-wdie profiling of gene expression in HEK293T cells following overexpression of wild type or catalytically mutant TET1-FL or TET1-CD
2014-06-04 | E-GEOD-49833 | biostudies-arrayexpress