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

基本信息

批准号：
10616780
负责人：
Yogesh Dwivedi
金额：
$ 59.23万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616780
关键词：
Adenosine Adult Affect Area Autopsy Binding Binding Sites Biological Biological Process Brain Brain Diseases Brain region Chromosome Mapping Code Complex Coping Behavior Data Development Disease Disease remission Environment Enzymes Etiology Family Gene Expression Gene Expression Regulation Genes Genetic Transcription Glucocorticoids Hippocampus 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 Persons Polyribosomes Post-Transcriptional Regulation Predisposition 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 Synapses Synaptic plasticity Synaptosomes Testing Therapeutic Intervention Tissues Transcript Transcriptional Regulation Translations Western Blotting 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 posttranscriptional preservation protein degradation protein expression recruit response severe mental illness statistics success tandem mass spectrometry tool transcriptome transcriptome sequencing

项目摘要

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.

尽管重度抑郁症（MDD）目前仍然是全球残疾的主要原因之一。随着治疗选择的增加，MDD 患者的缓解率非常低，因此，迫切需要确定其缓解率。众所周知，MDD 是一种在 MDD 中沉淀的生物底物，以开发有效的治疗方法。涉及对外部刺激的短期和长期适应不良过程，损害个体的能力到目前为止，还没有一致的假设可以完全解释这一点。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 病因学的核心。在这方面，最近出现了一种范式转变现象。通过表观转录组机制引入转录后基因调控的独特概念（最突出的是 N6-甲基腺苷 [m6A]），它不仅参与转录调节丰富，但具有影响成熟度、稳定性、本地化以及最重要的可用性的深远能力尽管转录率在高度“动态”和这种机制有助于对外部刺激的快速反应，微调蛋白质。可访问性，并执行局部控制，这对于刺激适应性基因表达至关重要。最近在突触可塑性以及小鼠的压力应对行为中得到了证实。初步数据表明，m6A mRNA 甲基化机制不仅在不同的大脑区域，但它们在操纵 m6A 甲基化和随后的过程中的表达和功能 MDD 大脑中特定转录本的表达是异常的，这使我们提出了一个总体方案。基于 m6A 甲基化的 mRNA 表观转录修饰可能充当动态调节因子的假设大脑区域特定方式的基因子集，通过影响特定的分子途径协调时尚，将参与 MDD 发病机制为了测试这一点，在健康的 dlPFC 和海马中。对照和匹配的 MDD 受试者，我们提出以下目标：1）检查 MDD 是否相关具有 m6A 甲基化机制的差异调节和独特的 m6A 甲基化谱大脑区域特定方式的表观转录组水平；2) 定义读者 YTH 家族的 MDD 相关作用蛋白质编码基因表观转录组转换中的蛋白质；3) 检查 m6A mRNA 甲基化的影响通过使用局部表观转录组库的树突可用性及其对 MDD 发病机制的贡献。创新的高分子方法，通过精确识别可翻译和转录的转录本的命运通过检查 m6A 甲基化的作用，通过特定 m6A 阅读器蛋白介导的不可翻译池在突触中，通过使用新颖的生物信息学工具分析数据，我们的研究具有高度创新性；发现独特的基于表观转录组的基因调控作为 MDD 发病机制的潜力并确定治疗干预的新目标。