Role of TET1-mediated epigenetic modulation in Alzheimer's disease.
Role of TET1-mediated epigenetic modulation in Alzheimer's disease.
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DOI：
10.1016/j.nbd.2023.106257
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发表时间：
2023-09
影响因子：
6.1
通讯作者：
Jin, Peng
中科院分区：
文献类型：
--
作者：
Armstrong, Matthew J.;Jin, Yulin;Vattathil, Selina M.;Huang, Yanting;Schroeder, Jason P.;Bennet, David A.;Qin, Zhaohui S.;Wingo, Thomas S.;Jin, Peng
阿尔茨海默病（AD）是一种神经退行性疾病，受环境、表观遗传和遗传因素的复杂相互作用影响。DNA甲基化（5 mC）和羟甲基化（5 hmC）是DNA修饰，作为基因表达的组织特异性和时间调节剂。泰特家族酶响应环境条件动态调节这些表观遗传修饰，将环境因素与基因表达联系起来。先前的表观遗传学研究已经确定了与AD相关的5 mC和5 hmC变化。在这项研究中，我们对一组早发性AD（EOAD）和对照样本进行了TET 1的靶向重测序。通过基因负荷分析，我们观察到与AD相关的罕见TET 1变体的显著富集（p = 0.04）。我们还分析了5 hmC在人死后的脑组织从AD和对照组。我们的分析确定了负责调节甲基化组的关键基因中的差异羟甲基化区域（DhMR）：TET 3，DNMT 3L，DNMT 3A和MECP 2。为了进一步研究Tet 1在AD发病机制中的作用，我们使用具有Tet 1 KO等位基因的5xFAD小鼠模型来研究Tet 1缺失如何影响AD发病机制。我们观察到与Tet 1丢失相关的神经病理学、5 hmC和RNA表达的显著变化，而行为改变不显著。Tet 1的缺失显著增加了5xFAD小鼠中的淀粉样蛋白斑块负荷（p = 0.044），并导致5xFAD小鼠中AD相关应激反应加剧的非显著趋势。在分子水平，我们发现显着DhMR丰富的基因参与的途径负责神经元投射组织，树突棘的发展和组织，髓鞘组装。RNA-Seq分析显示AD相关基因如Mpeg 1、Ctsd和Trem 2的表达显著增加。总之，我们的研究结果表明，泰特酶，特别是TET 1，调节甲基化，可能有助于AD的发病机制，作为泰特功能的损失增加AD相关的病理。
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.
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影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
10.5
作者：
Boudjelal, M;Taneja, R;Chambon, P
通讯作者：
Chambon, P
影响因子：
4
作者：
Cadena-del-Castilloa, Carla;Valdes-Quezada, Christian;Recillas-Targa, Felix
通讯作者：
Recillas-Targa, Felix
影响因子：
--
作者：
Coletta A;Pinney JW;Solís DY;Marsh J;Pettifer SR;Attwood TK
通讯作者：
Attwood TK
影响因子：
4.3
作者：
Al-Mahdawi S;Virmouni SA;Pook MA
通讯作者：
Pook MA