Tet-mediated Epigenetic Regulation in Alzheimer's Disease

Tet 介导的阿尔茨海默病表观遗传调控

• 批准号: 10617676
• 负责人: Matthew Armstrong
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617676
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Autopsy; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Cause of Death; Cell Culture Techniques; Cells; Characteristics; Chronic Disease; Complex; Cytosine; DNA; DNA Modification Process; Data; Dementia; Deterioration; Development; Disease; Disease Progression; Early Onset Alzheimer Disease; Environmental Risk Factor; Enzymes; Epigenetic Process; Equilibrium; Family; Follow-Up Studies; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Goals; Health; Health Personnel; Heritability; Hippocampus; Human; Immunohistochemistry; Impaired cognition; Individual; Investigation; Knock-out; Lead; Learning; Life; Link; Location; Measures; Mediating; Mediator; Memory; Methylation; Modification; Molecular; Mus; Mutation; Neurons; Nucleic Acid Regulatory Sequences; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Penetrance; Phenotype; Physiological; Play; Population; Prevalence; Process; Protein Family; Publications; Regulation; Research; Risk Factors; Role; Sampling; Senile Plaques; Site; Targeted Resequencing; Testing; Tetanus Helper Peptide; Tissues; United States; Variant; Work; cell type; cohort; demethylation; differential expression; epigenetic regulation; epigenome; gene repression; genetic variant; genome-wide; in vitro testing; insight; interest; loss of function; methylome; mouse model; mutant; nervous system disorder; neurodevelopment; neuroinflammation; neuron loss; neuropathology; neurotoxicity; novel; overexpression; oxidation; promoter; spatiotemporal; tau Proteins; tau aggregation; transcriptome sequencing; transcriptomics

PROJECT SUMMARY AD is caused by the progressive decay of neuronal connections ultimately leading to neuronal death. Loss of homeostatic neuronal function leads to severe cognitive decline in patients, inhibiting their ability to function in day-to-day life without extensive help from healthcare providers. The causes of AD are largely unknown; however, our current understanding recognizes that genetic, epigenetic, and environmental factors play a role in the disease. As epigenetic modifications are influenced by environmental factors and influence gene expression, they serve as a mediator between an individual’s genetic composition and phenotypic characteristics. Thus, epigenetic modifications hold promise to explain a significant portion of the missing heritability of AD, and several links between the epigenome, TET2, and AD have already been uncovered. Here we aim to identify novel TET2 variants associated with AD, and examine both how these variants and a reduction in abundance of TET2 lead to dysregulation of the methylome and how these alterations contribute to AD pathogenesis. Through examining the influence of TET on AD, we will advance our understanding on the role DNA hydroxymethylation plays in the brain regions most adversely affected by AD and how these changes influence gene expression, AD pathology, and learning and memory. Previously, our lab shed light on the role 5mC and 5hmC modifications play in neurodevelopment and several neurological disorders. Additionally, our lab identified differentially hydroxymethylated sites enriched in AD patients relative to controls and characterized the global 5hmC prevalence in an AD mouse model. More recently, we produced preliminary data to show enrichment of TET2 loss of function variants in individuals with early onset Alzheimer’s disease (~1.4% cases versus 0.12% controls). Building upon these previous findings, we will manipulate 5hmC modification profiles in an Alzheimer’s disease mouse model to investigate how dysregulation of TET enzymes contributes to AD pathogenesis. In conjunction with characterization of the methylome (measured via 5hmC Capture), we will analyze gene expression (measured via RNA-seq) and AD progression (measured via behavioral assays, and immunohistochemistry of Aβ plaques and neuronal populations) in wildtype and 5XFAD, a beta-amyloid plaque AD mouse model. These assays will be performed on tissues collected from the cortex and hippocampus. Our long-term goal is to identify novel AD associated TET2 mutations and how mutations in TET enzymes disrupt the balance of 5hmC signatures. Our findings may provide greater insight on genomic variants that contribute to AD risk, specific 5hmC profiles with the potential to be used as biomarkers for AD as well as variations in 5hmC profiles which confer AD pathogenicity or protection.

项目总结 AD是由神经元连接的进行性衰退引起的，最终导致神经元死亡。损失 动态平衡的神经元功能导致患者严重的认知能力下降，抑制他们在 在没有医疗保健提供者广泛帮助的情况下进行日常生活。阿尔茨海默病的病因在很大程度上是未知的； 然而，我们目前的理解承认，遗传、表观遗传和环境因素起着一定的作用 在疾病中。由于表观遗传修饰受环境因素和影响基因的影响 表达，它们在个体的遗传组成和表型之间起中介作用 特点。因此，表观遗传修饰有望解释很大一部分缺失 AD的遗传性，以及表观基因组、TET2和AD之间的几个联系已经被发现。这里 我们的目标是识别与AD相关的新的TET2变体，并研究这些变体和减少 大量的TET2导致甲基组的失调以及这些变化是如何导致AD的 发病机制。通过考察Tet对AD的影响，加深对Tet在AD中作用的认识 DNA羟甲基化在阿尔茨海默病最不利的大脑区域中的作用以及这些变化是如何发生的 影响基因表达、AD病理和学习记忆。此前，我们的实验室阐明了 5mC和5hmC修饰在神经发育和几种神经疾病中发挥作用。另外，我们的实验室 确定AD患者中与对照组相比丰富的不同羟甲基化位点，并表征 AD小鼠模型中的全球5hmC流行率。最近，我们制作了初步数据来表明 早发性阿尔茨海默病患者TET2功能缺失变异的丰富(~1.4%) 而对照组为0.12%)。在前面这些发现的基础上，我们将操作5hmC修改配置文件 一种阿尔茨海默病小鼠模型，研究Tet酶调节失调对AD的影响 发病机制。结合甲基组的表征(通过5hmC捕获测量)，我们将 分析基因表达(通过RNA-seq测量)和AD进展(通过行为分析测量，以及 野生型和β-淀粉样蛋白斑块中β斑块和神经元的免疫组织化学研究 广告鼠标模型。这些检测将在从大脑皮层和海马区收集的组织上进行。我们的 长期目标是确定与AD相关的新的TET2突变以及Tet酶的突变如何破坏 5hmc签名的余额。我们的发现可能提供对基因组变异的更深入的了解，这些变异有助于 AD风险，有可能被用作AD生物标志物的特定5hmC谱以及5hmC的变异 赋予AD致病性或保护性的配置文件。

项目成果

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

• DOI: 10.1016/j.nbd.2023.106257
• 发表时间: 2023-09
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 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
• 通讯作者: Jin, Peng