Novel regulatory role of nuclear miRNAs in repatterning the transcriptional and post-transcriptional dynamics in MDD brain

核 miRNA 在重模式 MDD 大脑转录和转录后动态中的新调节作用

基本信息

批准号：
10661760
负责人：
Yogesh Dwivedi
金额：
$ 70.92万
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：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661760
关键词：
3&apos Untranslated Regions Affect Agreement Area Aryl Hydrocarbon Receptor Back Binding Binding Sites Biotin Brain Brain Diseases Cell Nucleus Cell model Chromatin Code Complex Cytoplasm Data Development Disease Disease remission Elements Enzymes Epigenetic Process Etiology Exportins Functional disorder Gene Expression Genes Genetic Transcription Genome Mappings Glucocorticoid Receptor Hippocampus Importins In Vitro Individual Label Major Depressive Disorder Maps Mediating Messenger RNA MicroRNAs Microprocessor Molecular Neural Pathways Neurobiology Nuclear Nuclear Localization Signal Nuclear Translocation Oligonucleotides Pathogenesis Pathway Analysis Pattern Persons Prefrontal Cortex Process Promoter Regions Proteins RNA RNA Interference RNA purification RNA-Induced Silencing Complex Regulation Regulator Genes Research Research Personnel Ribonuclease III Ribonucleoproteins Ribonucleosides Role Sampling Series Signal Transduction Therapeutic Intervention Tissues Transcript Transcriptional Regulation Untranslated RNA chromatin immunoprecipitation crosslink crosslinking and immunoprecipitation sequencing depressive behavior effective therapy endonuclease exportin 1 protein gene environment interaction gene function genome-wide innovation interest mRNA Expression new therapeutic target novel overexpression posttranscriptional promoter severe mental illness success tool transcriptome transcriptome sequencing

项目摘要

The fine-tuning of transcriptional regulation by gene x environment interaction is central to maladaptive processes associated with major depressive disorder (MDD). Research over the past decade has provided strong support for the importance of epigenetic mechanisms in MDD pathogenesis. microRNAs (miRNAs), a class of small noncoding RNAs, are generating enormous interest not only as epigenetic mega-regulators of gene expression, but also for their role in disease pathophysiology and treatment targets. We and other investigators have shown differential regulation of miRNAs in the brain of MDD individuals. It is generally agreed that miRNAs mediate post-transcriptional gene silencing in the cytoplasm through seed sequence of miRNAs and complementary sequences in the 3′-untranslated regions (UTR) of target mRNAs via Argonaute (Ago)- based-RNA-induced silencing complex (miRISC). Recently, a paradigm-shifting phenomenon has been put forth with the concept of “nuclear localization” of select mature miRNAs. These miRNAs, containing unique set(s) of nuclear signals in the 3’ terminus, can shuttle back to nucleus from cytoplasm where they can regulate the expression of select nuclear pool of coding and non-coding RNA transcripts post-transcriptionally, but more remarkably, transcriptionally. At the transcription level, there is evidence of putative binding sites of mature miRNAs in the gene promoter regions with partial or perfect sequence complementarity, which enables nuclear miRNAs to regulate gene transcription, including primary(pri-)-miRNAs. Post-transcriptionally, nuclear miRNAs in conjunction with endonuclease Drosha, can target pri-miRNAs or can bind to 3’UTR region of nuclear coding transcripts via miRISC. The newly discovered mechanism poses an interesting possibility that within the nucleus, miRNAs may have the distinct capability of repatterning the gene transcription dynamics dramatically where they can not only regulate their own expression at pri- and precursor(pre)-miRNA levels, but also at the nuclear coding transcript level. This could be highly relevant in MDD-associated maladaptation processes. We propose an overarching hypothesis that a dynamic shift and nuclear enrichment of mature miRNAs driven by specific nuclear signals and their regulation of key pri-, pre-, and mature miRNAs, and coding genes within the nucleus, and consequent functional attributes, will be central to MDD pathogenesis. Using highly innovative approaches and well characterized and matched brain samples from MDD and non-psychiatric control subjects, we aim to determine: 1) the nuclear enrichment of miRNAs, cytosolic to nuclear shift, and their functional relevance; 2) possible mechanism(s) of miRNA translocation; 3) the unique transcriptional regulatory role of nuclear miRNAs in changing the promoter dynamics of target genes as a function of Ago1 complex; and 4) the unique role of nuclear miRNAs in modifying the processing of pri-miRNAs as a function of Drosha microprocessor complex. Our study is highly innovative and has the potential to uncover the unique role of nuclear miRNAs in redefining transcriptome as a mechanism in MDD etiology and identifying novel targets for therapeutic intervention.

基因X环境相互作用对转录调控的微调对于不良适应性是核心与主要抑郁症（MDD）相关的过程。过去十年中的研究提供了强烈支持表观遗传机制在MDD发病机理中的重要性。 microRNA（mirnas），a 一类小型非编码RNA，不仅引起巨大的兴趣基因表达，也是因为它们在疾病病理生理学和治疗靶标中的作用。我们和其他研究人员已经显示了MDD个体大脑中miRNA的差异调节。普遍同意 miRNA通过miRNA的种子序列介导细胞质中的转录后基因沉默以及通过Argonaute（AGO）的目标mRNA的3'-非翻译区域（UTR）中的互补序列 - 基于RNA诱导的沉默复合物（Mirisc）。最近，已经提出了一种范式转移现象以某些成熟miRNA的“核定位”的概念。这些miRNA，包含独特集 3'末端中的核信号可以从细胞质中穿梭回核us，可以在其中调节在转录后表达编码和非编码RNA转录本的精选核库，但更多值得注意的是，转录。在转录水平上，有证据表明成熟的假定结合位点具有部分或完美序列完整性的基因启动子区域中的miRNA，这使得核能 miRNA调节基因转录，包括原发性（PRI-） - miRNA。转录后，核miRNA 与核酸内切酶Drosha结合使用，可以瞄准pri-mirnas或可以与3'UTR核编码区域结合通过Mirisc进行笔录。新发现的机制提出了一种有趣的可能性，即在细胞核内， miRNA可能具有独特的能力，可以在其地点重现基因转录动力学不仅可以调节自己在Pri-pro-tirnor（Pre）-MIRNA水平上的表达，还可以在核编码上进行调节成绩单级别。这可能在与MDD相关的疾病过程中高度相关。我们建议一个总体假设是，由特定核驱动的成熟miRNA的动态转移和核酶信号及其调节核心，前和成熟的miRNA以及核中的编码基因，以及因此，功能属性将是MDD发病机理的核心。使用高度创新的方法来自MDD和非精神病患者的表征和匹配的大脑样本良好，我们的目标是确定：1）miRNA的核酶，胞质向核转移及其功能相关性； 2） miRNA易位的可能机制； 3）核miRNA的独特转录调节作用在更改靶基因的启动子动力学时，是AGO1复合物的函数； 4）核miRNA在修饰Pri-MiRNA的加工作为Drosha微处理器复合物的函数方面。我们的研究具有很高的创新性，并且有可能发现核miRNA在重新定义中的独特作用转录组作为MDD病因的机制，并确定了治疗干预的新靶标。