دورية أكاديمية
Alterations in DNA 5-hydroxymethylation patterns in the hippocampus of an experimental model of chronic epilepsy.
| العنوان: | Alterations in DNA 5-hydroxymethylation patterns in the hippocampus of an experimental model of chronic epilepsy. |
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| المؤلفون: | Bahabry R; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: bahabry@uab.edu., Hauser RM; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: rhauser@hudsonalpha.org., Sánchez RG; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: rgsanchez@ucsd.edu., Jago SS; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: sintjago@uab.edu., Ianov L; Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: lianov@uab.edu., Stuckey RJ; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: rjs0012@uab.edu., Parrish RR; Department of Cell Biology and Physiology, Brigham Young University, Provo, UT, United States of America. Electronic address: ryley_parrish@byu.edu., Ver Hoef L; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: lverhoef@uabmc.edu., Lubin FD; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States of America. Electronic address: flubin@uab.edu. |
| المصدر: | Neurobiology of disease [Neurobiol Dis] 2024 Oct 01; Vol. 200, pp. 106638. Date of Electronic Publication: 2024 Aug 13. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: San Diego, CA : Academic Press Original Publication: Oxford : Blackwell Science, c1994- |
| مواضيع طبية MeSH: | Hippocampus*/metabolism , 5-Methylcytosine*/analogs & derivatives , 5-Methylcytosine*/metabolism , Epilepsy, Temporal Lobe*/metabolism , Epilepsy, Temporal Lobe*/genetics , DNA Methylation* , Disease Models, Animal*, Animals ; Male ; Humans ; Rats ; Rats, Sprague-Dawley ; Female ; Epigenesis, Genetic ; Adult ; Kainic Acid |
| مستخلص: | Temporal lobe epilepsy (TLE) is a type of focal epilepsy characterized by spontaneous recurrent seizures originating from the hippocampus. The epigenetic reprogramming hypothesis of epileptogenesis suggests that the development of TLE is associated with alterations in gene transcription changes resulting in a hyperexcitable network in TLE. DNA 5-methylcytosine (5-mC) is an epigenetic mechanism that has been associated with chronic epilepsy. However, the contribution of 5-hydroxymethylcytosine (5-hmC), a product of 5-mC demethylation by the Ten-Eleven Translocation (TET) family proteins in chronic TLE is poorly understood. 5-hmC is abundant in the brain and acts as a stable epigenetic mark altering gene expression through several mechanisms. Here, we found that the levels of bulk DNA 5-hmC but not 5-mC were significantly reduced in the hippocampus of human TLE patients and in the kainic acid (KA) TLE rat model. Using 5-hmC hMeDIP-sequencing, we characterized 5-hmC distribution across the genome and found bidirectional regulation of 5-hmC at intergenic regions within gene bodies. We found that hypohydroxymethylated 5-hmC intergenic regions were associated with several epilepsy-related genes, including Gal, SV2, and Kcnj11 and hyperdroxymethylation 5-hmC intergenic regions were associated with Gad65, TLR4, and Bdnf gene expression. Mechanistically, Tet1 knockdown in the hippocampus was sufficient to decrease 5-hmC levels and increase seizure susceptibility following KA administration. In contrast, Tet1 overexpression in the hippocampus resulted in increased 5-hmC levels associated with improved seizure resiliency in response to KA. These findings suggest an important role for 5-hmC as an epigenetic regulator of epilepsy that can be manipulated to influence seizure outcomes. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Farah Lubin reports financial support was provided by National Institute of Neurological Disorders and Stroke. Lawrence Ver Hoef reports was provided by National Institute of Neurological Disorders and Stroke. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Update of: bioRxiv. 2023 Oct 05:2023.10.03.560698. doi: 10.1101/2023.10.03.560698. (PMID: 37873276) |
| فهرسة مساهمة: | Keywords: Bdnf; DNA methylation; Epigenetics; Epilepsy; Hydroxymethylation; Sequencing; TET; hMeDIP |
| المشرفين على المادة: | 6R795CQT4H (5-Methylcytosine) 1123-95-1 (5-hydroxymethylcytosine) SIV03811UC (Kainic Acid) |
| تواريخ الأحداث: | Date Created: 20240814 Date Completed: 20240912 Latest Revision: 20240912 |
| رمز التحديث: | 20240913 |
| DOI: | 10.1016/j.nbd.2024.106638 |
| PMID: | 39142613 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1095-953X |
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| DOI: | 10.1016/j.nbd.2024.106638 |