Epigenomic Profile and Function of H3.3 Variant During Sensitive Period of Neurod

Neurod敏感期H3.3变异体的表观基因组谱和功能

• 批准号: 8305490
• 负责人: CHARLES DAVID ALLIS
• 金额: $ 41.87万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305490
• 关键词: Adult; Affect; American; Amino Acids; Animals; Antibodies; Behavior; Bioinformatics; Biological; Brain; Brain region; Cell Cycle; Cell physiology; Cells; ChIP-seq; Chromatin; Chromatin Modeling; Chromatin Structure; Cognition; Cognitive; Collaborations; DNA Sequence; DNA biosynthesis; Data; Deposition; Development; Developmental Gene; Enhancers; Environment; Epigenetic Process; Eukaryotic Cell; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genomics; Goals; Hippocampus (Brain); Histone H3; Histone H3.3; Histones; Impairment; Individual; Institution; Knock-in Mouse; Knockout Mice; Lead; Life; Life Experience; Link; Maintenance; Mediating; Medical; Mental disorders; Mitotic; Modification; Molecular Profiling; Morphology; Mouse Strains; Mus; Nervous system structure; Neurons; Neurosciences; Pattern; Process; Proteins; Regulation; Regulatory Element; Research; Role; Series; Social Behavior; Source; Staging; Stimulus; Structure; Technology; Testing; Therapeutic Intervention; Time; Tissues; Variant; Work; base; combinatorial; critical period; embryonic stem cell; environmental enrichment for laboratory animals; epigenetic variation; epigenomics; experience; gain of function; gene environment interaction; genome-wide; histone modification; in vivo; insight; loss of function; multidisciplinary; neurodevelopment; novel; promoter; relating to nervous system; research study; response; telomere; tool

DESCRIPTION (provided by applicant): Neurodevelopment is an intricate and dynamic process involving gene-environment interactions, which result in a series of changes in gene expression, cellular function, circuit formation, neuronal morphology and behavior. Epigenetic and chromatin-based modifications mediate distinct cellular gene expression profiles in vivo without directly affecting the DNA sequence in response to environmental stimuli. Exciting new research indicates that in addition to nucleosomal remodeling and covalent histone modifications, eukaryotic cells generate variation in chromatin structure through the introduction of variant histone proteins. Emerging evidence indicates that H3.3 represents an ideal chromatin mark for efficiently profiling dynamic changes in the epigenomic landscape during critical periods of transcriptional maintenance and regulation. We therefore will explore potential novel links between H3.3 specific variant localization and subsequent downstream patterns of gene expression during longitudinal stages of neurodevelopment. Our central hypothesis is that -- environmental stimuli experienced during critical periods of neurodevelopment are associated with robust changes in tissue specific H3.3 deposition profiles, such that comprehensive longitudinal analyses of the H3.3 epigenome promise to provide fundamentally novel insight into the impact of early environmental influences on the development of altered vulnerabilities to mental disorders during adulthood. We seek to test this working hypothesis in the following three interrelated Specific Aims: 1) Identify longitudinal histone H3.3 localization patterns in brain throughout neurodevelopment. We aim to perform unbiased epigenome-wide (ChIP-seq) analyses of histone H3.3 variant localization in the developing and adult brain, with specific emphasis on brain regions located within the limbic circuitry (e.g. hippocampus and cortex), using tagged H3.3 knock-in mice or a specific H3.3 antibody under standard basal conditions. 2) Examine the impact of early life experiences on histone H3.3 regulation and relocalization in brain. We aim to examine the ability of early life environmental enrichment to redirect H3.3 deposition throughout the chromatin template, thereby influencing normal patterns of developmental gene regulation. 3) Determine the functional relevance of H3.3 deposition by means of regulated loss-of-function and gain-of-function studies. We aim to generate complementary mouse lines and tools to study, and conduct experiments with these animals to explore the biological role of H3.3 variant deposition in guiding developmentally influenced cognitive and social behaviors. Collectively our studies will provide novel and critical information regarding the epigenome across neurodevelopment. Identification of genes and gene networks with altered epigenetic status will help to better describe the "epigenetic landscape" during sensitive periods of brain development and pinpoint novel targets for therapeutic intervention related to mental disorders.

描述（由申请人提供）：神经发育是一个复杂的动态过程，涉及基因-环境相互作用，导致基因表达、细胞功能、回路形成、神经元形态和行为的一系列变化。表观遗传和基于染色质的修饰介导体内不同的细胞基因表达谱，而不直接影响响应环境刺激的 DNA 序列。令人兴奋的新研究表明，除了核小体重塑和共价组蛋白修饰之外，真核细胞还通过引入变体组蛋白来产生染色质结构的变化。新的证据表明，H3.3 是一种理想的染色质标记，可有效分析转录维持和调控关键时期表观基因组景观的动态变化。因此，我们将探索 H3.3 特异性变异定位与神经发育纵向阶段后续基因表达下游模式之间的潜在新联系。我们的中心假设是——神经发育关键时期经历的环境刺激与组织特异性 H3.3 沉积谱的剧烈变化相关，因此 H3.3 表观基因组的全面纵向分析有望为神经发育的影响提供全新的见解。早期环境对成年期精神障碍脆弱性的发展产生影响。我们试图通过以下三个相互关联的具体目标来检验这一工作假设：1) 识别整个神经发育过程中大脑中的纵向组蛋白 H3.3 定位模式。我们的目标是使用标记的 H3 对发育中和成人大脑中的组蛋白 H3.3 变异定位进行无偏倚的全表观基因组 (ChIP-seq) 分析，特别强调位于边缘回路（例如海马和皮质）内的大脑区域。标准基础条件下的 3 只敲入小鼠或特定 H3.3 抗体。 2) 检查早期生活经历对大脑中组蛋白 H3.3 调节和重定位的影响。我们的目的是检查早期生命环境富集在整个染色质模板中重定向 H3.3 沉积的能力，从而影响发育基因调控的正常模式。 3) 通过受监管的功能丧失和功能获得研究来确定 H3.3 沉积的功能相关性。我们的目标是生成互补的小鼠品系和工具来研究，并用这些动物进行实验，以探索 H3.3 变异沉积在指导发育影响的认知和社会行为中的生物学作用。总的来说，我们的研究将提供有关整个神经发育的表观基因组的新颖且关键的信息。识别表观遗传状态改变的基因和基因网络将有助于更好地描述大脑发育敏感时期的“表观遗传景观”，并确定与精神障碍相关的治疗干预的新靶标。