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

• 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
• 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

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.

重性抑郁症（MDD），在其他情绪障碍，是一种高度异质性，使人衰弱的疾病 影响着全世界数百万人;然而，大脑功能的破坏会导致MDD的发生， 人们对此知之甚少，目前的治疗效果有限。尽管偶然发现了 60多年前，单胺相关抗抑郁药（AD;例如，SSRIs）仍然是第一行 许多MDD患者的治疗，但在开始治疗和症状缓解之间的长时间延迟， 以及较低的缓解率，鼓励了进一步的研究，试图确定更多的 直接的治疗目标。特别是血清素，被认为在神经元可塑性中起关键作用， 其信号转导的改变与MDD的发展和治疗有关。虽然泡状 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， 证明了囊外单胺在两种单胺能神经细胞核中的额外存在。 神经元，以及来自单胺能投射区的神经元;然而， 核5-羟色胺是否独立于神经传递发挥作用。血清素以前曾被 显示通过组织转氨酶2的转酰胺作用与某些蛋白质形成共价键 酶，一个被称为乙酰丙酮化的过程。我们的实验室最近鉴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4三甲基化的组合; H3 K4 me 3Q 5ser）， 用于体内腺苷酰化的新底物。此外，我们最近发现，H3 K4 me 3Q 5ser是显着 在被诊断患有以下疾病的人类受试者死后中缝背核（DRN）中， 在人类抑郁症（慢性社会失败压力）的病因学相关啮齿动物模型中- 这些现象被治疗有效的慢性AD治疗完全逆转。因此我们 假设组蛋白乙酰化可能建立了神经元基因表达的重要模式， 这是一种分子机制，如果受到慢性压力（或 其他改变血清素动力学的操作）可能导致异常的可塑性和对 抑郁和/或焦虑样行为。这种机制也可以解释SSRI的延迟疗效 广告.因此，我们计划在以下目标中评估这些可能性：1）进行性别和细胞类型特异性 正常与应激脑中H3 K4 me 3Q 5ser的表观基因组分析，包括基础和SSRIs背景下; 2)评估组蛋白H3的细胞类型特异性操作的转录和行为影响 研究组蛋白与应激诱导的行为之间的新的机制联系 慢性应激后脆弱神经元的乙酰化和前起始复合物的形成。这项工作 承诺提供关键的见解，如何血清素，独立于神经传递，有助于 成年期神经元可塑性，以及它如何影响MDD/应激相关表型的发作。