Molecular studies of neural histone monoaminylation in normal and aberrant brain plasticity

正常和异常大脑可塑性中神经组蛋白单胺化的分子研究

基本信息

批准号：
10310479
负责人：
Ian S. Maze
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310479
关键词：
Adult Affect Animals Antibodies Antidepressive Agents Autopsy Behavior Behavioral Biochemical Brain Cell Nucleus Cells ChIP-seq Chromatin Chromatin Structure Chronic Chronic stress Complex Coupled Data Development Diagnosis Disease Disease model Disease remission Effectiveness Enzymes Epigenetic Process Etiology Female Fluorescence-Activated Cell Sorting Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Germ Cells Glutamates Glutamine Histone H3 Histones Human Individual Investigation Laboratories Lead Life Experience Link Lysine Major Depressive Disorder Medial Mediating Mediation Mental Depression Mental disorders Methylation Modification Molecular Monoamine Oxidase Inhibitors Mood Disorders Moods Mus Neurologic Neuronal Dysfunction Neuronal Plasticity Neurons Neurosciences Nuclear Outcome Pattern Pharmacology Phenotype Physiological Play Population Post-Translational Protein Processing Predisposition Prefrontal Cortex Process Proteins Public Health Regulation Rodent Model Role Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Signal Transduction Stress Syndrome TAF1 gene TAF3 gene Traumatic Stress Disorders Viral Vector Work anxiety-like behavior base behavioral response cell type chromatin immunoprecipitation cognitive process covalent bond depressive behavior depressive symptoms dorsal raphe nucleus epigenomics excitatory neuron gain of function gene network genome-wide histone modification human model human subject in vivo insight male monoamine mouse model nervous system disorder neuronal patterning neurotransmission next generation sequencing novel programs promoter recruit relating to nervous system response sex social defeat social stress stress related disorder therapeutic development therapeutic target therapeutically effective tool transcription factor transcriptome sequencing transglutaminase 2 vector

项目摘要

Major depressive disorder (MDD), among other mood disorders, is a highly heterogeneous, debilitating illness that affects millions of individuals worldwide; however, disruptions in brain function that precipitate MDD are poorly understood, and current treatments have limited efficacy. Despite being serendipitously discovered more than 60 years ago, monoamine associated antidepressants (ADs; e.g., SSRIs) remain the first line of therapy for many with MDD, yet long delays between initiation of treatment and symptomatic alleviation, as well as low remission rates, have encouraged further investigations in an attempt to identify more direct therapeutic targets. Serotonin, in particular, is thought to play a critical role in neuronal plasticity, with alterations in its signaling implicated in both the development and treatment of MDD. Although vesicular packaging of serotonin is essential for neurotransmission, recent data, including from our own laboratory, have demonstrated the additional presence of extravesicular monoamines in the nucleus of both monoaminergic neurons, as well as in neurons from monoaminergic projection regions; it has remained unclear, however, whether nuclear serotonin may play roles independent of neurotransmission. Serotonin has previously been shown to form covalent bonds with certain proteins via transamidation by the tissue Transglutaminase 2 enzyme, a process known as serotonylation. Our laboratory recently identified and fully characterized histone proteins (specifically histone H3 glutamine 5 in combination with lysine 4 tri-methylation; H3K4me3Q5ser) as novel substrates for serotonylation in vivo. Furthermore, we recently found that H3K4me3Q5ser is significantly altered in its expression in both postmortem dorsal raphe nucleus (DRN) of human subjects diagnosed with MDD, and in an etiologically relevant rodent model of human depression (chronic social defeat stress)– phenomena that are completely reversed by therapeutically effective chronic AD treatments. Thus, we hypothesize that histone serotonylation likely establishes important patterns of neuronal gene expression in brain that are necessary for normal transcription, a molecular mechanism that if perturbed by chronic stress (or other manipulations that alter serotonin dynamics) may lead to aberrant plasticity and vulnerability to depressive- and/or anxiety-like behaviors. Such a mechanism may also explain the delayed efficacy of SSRI ADs. We therefore plan to assess these possibilities in the following Aims: 1) perform sex and cell-type specific epigenomic analyses of H3K4me3Q5ser in normal vs. stressed brain, both basally and in the context of SSRIs; 2) assess the transcriptional and behavioral impacts of cell-type specific manipulations of histone H3 serotonylation on stress-induced behaviors; and 3) explore novel mechanistic links between histone serotonylation and pre-initiation complex formation in vulnerable neurons following chronic stress. This work promises to provide critical insights into how serotonin, independently from neurotransmission, contributes to adulthood neuronal plasticity, as well as how it may influence on the onset of MDD/stress related phenotypes.

重度抑郁症（MDD），除其他情绪障碍外，是一种高度异质，使人衰弱的疾病这影响了全球数百万个人；但是，大脑功能的干扰是宝贵的MDD 理解不足，目前的治疗效率有限。尽管被偶然发现 60多年前，单胺相关的抗抑郁药（AD;例如SSRI）仍然是第一行许多具有MDD的人的治疗以及低缓解率，也鼓励进一步调查，以识别更多直接治疗靶标。尤其是5-羟色胺在神经元可塑性中起着至关重要的作用，其信号传导的改变涉及MDD的发展和处理。虽然囊泡 5-羟色胺的包装对于神经传递至关重要，最近的数据，包括我们自己的实验室，证明了两种单胺能的核中额外的跨乳房单胺神经元以及来自单胺能投射区域的神经元；但是，目前尚不清楚核5-羟色胺是否可以独立于神经传递而扮演角色。 5-羟色胺以前已经显示通过组织转谷氨酰胺酶2通过透射型与某些蛋白质形成共价键酶，一种称为血清素化的过程。我们的实验室最近确定并完全表征了组蛋白蛋白质（特别是组蛋白H3谷氨酰胺5与赖氨酸4三甲基化相结合； H3K4me3Q5SER）体内详细的血清元化底物。此外，我们最近发现H3K4me3q5ser显着在诊断为诊断为人类受试者的两位尸体后raphe核的表达改变了其表达 MDD，以及与病因相关的人类抑郁模型（慢性社会失败压力） - 通过热有效的慢性广告处理完全逆转的现象。那，我们假设组蛋白的血统可能建立了神经元基因表达的重要模式正常转录所必需的大脑，这是一种分子机制，如果被慢性应激扰动（或改变5-羟色胺动力学的其他操作）可能导致异常可塑性和脆弱性抑郁和/或类似焦虑的行为。这种机制也可以解释SSRI的延迟效率广告。因此，我们计划在以下目的中评估这些可能性：1）执行性别和细胞类型的特异性基本和在SSRI的背景下，在正常和压力大脑中对H3K4Me3Q5SER的表观基因组学分析； 2）评估组蛋白H3的细胞类型特异性操纵的转录和行为影响关于压力引起的行为的血清素化； 3）探索组蛋白之间的新机械联系慢性应激后，脆弱神经元中的血清素化和发射复合物的形成。这项工作有望提供有关5-羟色胺如何独立于神经递质的批判性见解成年神经元的可塑性，以及它如何影响与MDD/应力相关表型的发作。