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: 8179528
• 负责人: CHARLES DAVID ALLIS
• 金额: $ 42.64万
• 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/8179528
• 关键词: Adult; Affect; American; Amino Acids; Animals; Antibodies; Behavior; Bioinformatics; Biological; Brain; Brain region; Cell Cycle; Cell physiology; Cells; 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 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. PUBLIC HEALTH RELEVANCE: The overall goal of this multidisciplinary, collaborative proposal is to apply state-of the-art gene and chromatin arraying technologies to better understand epigenetic variations mediating normal neural development, as well as those acting during sensitive periods of neurodevelopmental that may predispose individuals to the onset of mental illness. Mental disorders are devastating illnesses, which impact a considerable number of Americans and for which there are few treatments that adequately reverse neuronal impairment. Epigenetic reprogramming via exchange of specific histone variants, especially during times in which cells in the brain are not replicating, may represent a central mechanism for regulation of gene expression during sensitive periods of brain development.

描述（由申请人提供）：神经发育是一个复杂而动态的过程，涉及基因环境相互作用，导致基因表达，细胞功能，电路形成，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了体内不同的细胞基因表达谱，而无需直接影响对环境刺激的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外，真核细胞还通过引入变体组蛋白蛋白来产生染色质结构的变化。新兴的证据表明，H3.3代表了在转录维持和调节的关键时期有效地分析表观基因组景观动态变化的理想染色质标记。因此，我们将探索神经发育纵向期间H3.3特定变异定位与随后的基因表达下游模式之间的潜在新联系。我们的核心假设是 - 神经发育的关键时期经历的环境刺激与组织特异性H3.3沉积曲线的耐用变化有关，因此H3.3表观基因组的全面纵向分析有望从根本上提供有关对基本上新颖的洞察力的洞察力。早期环境对成年期间精神障碍脆弱性改变的发展产生影响。我们试图在以下三个相互关联的特定目的中检验这一工作假设：1）确定整个神经发育中大脑中纵向组蛋白H3.3的定位模式。我们旨在对发展中和成人大脑中的组蛋白H3.3变体定位进行无偏见的整个表观依性（CHIP-SEQ）分析，并使用标记的H3对位于边缘电路（例如海马和皮质）内的大脑区域（例如海马和皮质）进行了特定的重视。在标准基础条件下3敲入小鼠或特定的H3.3抗体。 2）检查早期生活经验对组蛋白H3.3大脑调节和重新定位的影响。我们旨在检查早期生活环境富集重定向H3.3在整个染色质模板中沉积的能力，从而影响发育基因调控的正常模式。 3）通过受调节的功能丧失和功能增益研究来确定H3.3沉积的功能相关性。我们旨在生成互补的小鼠线条和工具来研究并对这些动物进行实验，以探索H3.3变体沉积在指导发展影响认知和社会行为方面的生物学作用。我们的研究集体将提供有关神经发育中表观基因组的新颖和关键信息。鉴定具有改变表观遗传状态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”，并确定与精神障碍有关的治疗干预的新型目标。 公共卫生相关性：这项多学科，协作提案的总体目标是应用最新的基因和染色质数组阵列技术，以更好地了解介导正常神经发育的表观遗传变异，以及那些在敏感时期的表现，可能会使您倾向于易感性神经发育。个体开始精神疾病。精神障碍是毁灭性的疾病，这会影响大量美国人，并且很少有治疗能够充分逆转神经元障碍。通过交换特定组蛋白变异的表观遗传重编程，尤其是在大脑中未复制细胞的时期，可能代表了调节大脑发育敏感时期基因表达的中心机制。