ArticleStroke2025
TET3-Interacting LncRNA TILR Is Essential for DNA Hydroxymethylation-Mediated Neuroprotection After Ischemic Stroke.
Article in Stroke, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Focal ischemia induces genome-wide accumulation of R-loops in the brain.Molecular therapy. Nucleic acids · 2026Article
- Epigenetic Mechanisms Regulating Ferroptosis in Ischemic Stroke: From Pathogenesis to Therapeutic Targets.Cellular and molecular neurobiology · 2026Review
- Targeting Epigenetics in Ischemic Stroke: From Mechanisms to Therapeutics.Current neuropharmacology · 2026Review
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5 authors.
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Abstract
backgroundEpigenetic modifications 5-methylcytosine and 5-hydroxymethylcytosine in DNA regulate neuronal survival under ischemic stress. We previously showed that TET3 (ten-eleven translocase 3)-mediated 5-methylcytosine to 5-hydroxymethylcytosine conversion induces neuroprotective gene transcription after stroke. As TET3 neuronal isoform lacks the DNA-binding domain, how TET3 drives 5-hydroxymethylcytosine-mediated transcriptional induction in the ischemic brain remains unclear. Long noncoding RNAs (lncRNAs) act as structural scaffolds to recruit chromatin-modifying proteins and other RNAs to specific genomic loci. However, whether TET3 requires an lncRNA to drive DNA hydroxymethylation in the ischemic brain is unknown.
methodsAdult male and female mice were subjected to transient middle cerebral artery occlusion. TET3-bound lncRNAs were immunoprecipitated from peri-infarct cortex, and TILR (TET3-interacting lncRNA; AK020504) identified was inhibited with small interfering RNA injected at 5 minutes of reperfusion. Ascorbate was administered at 30 minutes of reperfusion to induce TET3 activity. Poststroke DNA hydroxymethylation was assessed with hydroxymethylation DNA immunoprecipitation sequencing, and sensorimotor deficits, and infarct volume were evaluated between days 1 and 7 of reperfusion.
resultsTILR binds to TET3 with high affinity and was significantly upregulated in the peri-infarct cortex at 12 hours of reperfusion. Knockdown of TILR increased the infarct volume and reduced the motor function recovery after transient middle cerebral artery occlusion, in a TET3-dependent manner. On contrary, TET3 activation by ascorbate decreased brain damage and improved motor function recovery after ischemia. However, ascorbate-induced postischemic protection was abrogated by TILR knockdown. Genome-wide profiling showed that ascorbate increases the number of differentially hydroxymethylated regions in the poststroke genome, a neuroprotective effect that is reversed by TILR knockdown. Moreover, TILR inhibition significantly reduced the DNA hydroxymethylation in the intergenic regions associated with enhancers, super enhancers, and the promoters of other lncRNAs, microRNAs, and PIWI-interacting RNAs.
conclusionsThese findings highlight the essential role of TILR in TET3-mediated 5-hydroxymethylcytosine-dependent epigenetic reprogramming in the ischemic brain.
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