Epitranscriptomic Mapping of Novel N6-Adenosine-based RNA Methylation in MDD Brain

MDD 脑中新型 N6-腺苷 RNA 甲基化的表观转录组图谱

• 批准号: 9978955
• 负责人: Yogesh Dwivedi
• 金额: $ 61.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978955
• 关键词: Adenosine; Adult; Affect; Area; Autopsy; Binding Sites; Biological; Biological Process; Brain; Brain Diseases; Brain region; Code; Complex; Coping Behavior; Data; Data Analyses; Development; Disease; Disease remission; Environment; Enzymes; Etiology; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucocorticoids; Hippocampus (Brain); Human; Immunoprecipitation; Impairment; Individual; Lead; Liquid Chromatography; Major Depressive Disorder; Maps; Mediating; Mental Depression; Messenger RNA; Methylation; Modification; Molecular; Mus; Neurobiology; Nuclear; Ontology; Output; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Polyribosomes; Post-Transcriptional Regulation; Prefrontal Cortex; Process; Proteins; RNA; RNA Binding; RNA methylation; Rattus; Reader; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleosides; Role; Sampling; Stimulus; Stress; Stress and Coping; Structure; Synapses; Synaptic plasticity; Synaptosomes; Testing; Therapeutic Intervention; Tissues; Transcript; Transcriptional Regulation; Translations; Western Blotting; base; bioinformatics tool; cohort; crosslinking and immunoprecipitation sequencing; demethylation; depressive behavior; differential expression; disability; effective therapy; epitranscriptome; epitranscriptomics; gene environment interaction; innovation; mRNA Expression; new therapeutic target; novel; preservation; protein degradation; protein expression; recruit; response; severe mental illness; statistics; success; tandem mass spectrometry; tool; transcriptome; transcriptome sequencing

Major depressive disorder (MDD) currently remains one of the leading causes of global disability. Despite the rise in treatment options, remission rates in MDD patients are very low. Thus, there is critical need to identify the biological substrates that precipitate in MDD in order to develop effective therapy. It is widely known that MDD involves short- and long-term maladaptive processes to external stimuli, impairing the ability of individuals to appropriately interact with the environment. So far, there is no coherent hypothesis that can fully explain this phenomenon. Increasing evidence suggests that fine-tuning of transcriptional regulation by gene-environment interaction is central to the etiology of MDD. In this regard, a paradigm shifting phenomenon has recently been introduced with the unique concept of post-transcriptional gene regulation through epitranscriptomic mechanism (most prominently being N6-methyladenosine [m6A]) which is not only involved in the regulation of transcript abundance but has the profound ability to impact maturity, stability, localization, and most importantly, availability of “select” gene transcripts to protein translation despite varying transcription rates in a highly “dynamic” and “reversible” fashion. This mechanism facilitates quick response to external stimuli, fine-tunes protein accessibility, and executes localized control, which is critical to stimulus-adaptive gene expression. Their roles have recently been shown in synaptic plasticity as well as in the stress coping behavior of mice. Our own preliminary data demonstrate that not only is m6A mRNA methylation machinery differentially expressed in various brain areas, but their expression and functions in manipulating m6A methylation and subsequent expression of specific transcripts are aberrant in the MDD brain. This has led us to propose an overarching hypothesis that m6A methylation-based epitranscriptomic modification of mRNAs may act as a dynamic regulator of a subset of genes in a brain region specific manner, which, by affecting specific molecular pathways in a coordinated fashion, will participate in MDD pathogenesis. To test this, in dlPFC and hippocampus from healthy controls and well-matched MDD subjects, we propose the following aims: 1) Examine whether MDD is associated with differential regulation of m6A methylation machinery and distinctive m6A methylation profile at the epitranscriptomic level in brain region specific manner; 2) Define MDD associated role of YTH family of reader proteins in epitranscriptomic turnover of protein coding genes; 3) Examine the impact of m6A mRNA methylation on dendritic availability of local epitranscriptomic pool and their contribution to MDD pathogenesis. By using highly innovative molecular approaches, by precisely identifying the fate of the transcripts in translatable and non-translatable pools mediated through specific m6A reader proteins, by examining the role of m6A methylation at the synapse, and by analyzing data using novel bioinformatics tools, our study is highly innovative; it has the potential to discover unique epitranscriptome-based gene regulation as a mechanism in MDD etiopathogenesis and identify novel targets for therapeutic intervention.

主要抑郁症（MDD）目前仍然是全球残疾的主要原因之一。尽管有 治疗方案的增加，MDD患者的缓解率非常低。那是迫切需要确定 在MDD中沉淀以开发有效治疗的生物底物。众所周知，MDD 涉及到外部刺激的短期和长期不良适应过程，从而损害了个人的能力 适当与环境互动。到目前为止，还没有一致的假设可以完全解释这一点 现象。越来越多的证据表明，基因环境对转录调控进行微调 相互作用是MDD病因的核心。在这方面，范式转移现象最近是 引入了通过表参数机制的转录后基因调节的独特概念 （最突出的是N6-甲基读二胺[M6A]），不仅参与了转录本的调节 抽象，但具有影响到期，稳定性，本地化的深刻能力，最重要的是可用性 在高度“动态”和 “可逆”时尚。这种机制促进了对外部刺激的快速反应，微型蛋白 可访问性并执行局部控制，这对于刺激自适应基因表达至关重要。他们的角色 最近以突触可塑性以及小鼠的应力应对行为显示。我们自己的 初步数据表明，不仅M6A mRNA甲基化机制在 各种大脑区域，但它们在操纵M6A甲基化和随后的表达和功能 特定转录本的表达在MDD脑中异常。这使我们提出了一个总体 假设mRNA的基于M6a甲基化的表面参考修饰可能是动态调节剂 以大脑区域特异性方式的基因子集的子集，该方式通过影响A中的特定分子途径 协调的方式将参加MDD发病机理。为此，在DLPFC和健康的海马中进行测试 控件和匹配良好的MDD受试者，我们提出以下目的：1）检查MDD是否相关 在M6A甲基化机械和独特的M6A甲基化谱的调节差异 大脑区域特定方式的表面参考水平； 2）定义读者读者家族的MDD相关角色 蛋白质编码基因的表面转录组流体的蛋白质； 3）检查M6A mRNA甲基化的影响 关于局部表演池的树突状可用性及其对MDD发病机理的贡献。通过使用 高度创新的分子方法，通过精确识别可翻译和 通过特定的M6A读取器蛋白介导的不可转化的池，通过检查M6A甲基化的作用 在突触中，通过使用新颖的生物信息学工具进行了分析，我们的研究具有很高的创新性。它有 潜在发现基于同意组的独特基因调节作为MDD疗法发生的一种机制 并确定用于治疗干预的新目标。