Role of TET1-mediated epigenetic modulation in Alzheimer's disease.

Autor: Armstrong MJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Jin Y; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Vattathil SM; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Huang Y; Department of Computer Science, Emory University, Atlanta, GA 30322, USA., Schroeder JP; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Bennet DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA., Qin ZS; Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA., Wingo TS; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Jin P; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: peng.jin@emory.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2023 Sep; Vol. 185, pp. 106257. Date of Electronic Publication: 2023 Aug 08.
DOI: 10.1016/j.nbd.2023.106257
Abstrakt: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by a complex interplay of environmental, epigenetic, and genetic factors. DNA methylation (5mC) and hydroxymethylation (5hmC) are DNA modifications that serve as tissue-specific and temporal regulators of gene expression. TET family enzymes dynamically regulate these epigenetic modifications in response to environmental conditions, connecting environmental factors with gene expression. Previous epigenetic studies have identified 5mC and 5hmC changes associated with AD. In this study, we performed targeted resequencing of TET1 on a cohort of early-onset AD (EOAD) and control samples. Through gene-wise burden analysis, we observed significant enrichment of rare TET1 variants associated with AD (p = 0.04). We also profiled 5hmC in human postmortem brain tissues from AD and control groups. Our analysis identified differentially hydroxymethylated regions (DhMRs) in key genes responsible for regulating the methylome: TET3, DNMT3L, DNMT3A, and MECP2. To further investigate the role of Tet1 in AD pathogenesis, we used the 5xFAD mouse model with a Tet1 KO allele to examine how Tet1 loss influences AD pathogenesis. We observed significant changes in neuropathology, 5hmC, and RNA expression associated with Tet1 loss, while the behavioral alterations were not significant. The loss of Tet1 significantly increased amyloid plaque burden in the 5xFAD mouse (p = 0.044) and lead to a non-significant trend towards exacerbated AD-associated stress response in 5xFAD mice. At the molecular level, we found significant DhMRs enriched in genes involved in pathways responsible for neuronal projection organization, dendritic spine development and organization, and myelin assembly. RNA-Seq analysis revealed a significant increase in the expression of AD-associated genes such as Mpeg1, Ctsd, and Trem2. In conclusion, our results suggest that TET enzymes, particularly TET1, which regulate the methylome, may contribute to AD pathogenesis, as the loss of TET function increases AD-associated pathology.
Competing Interests: Declaration of Competing Interest The authors declare no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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