Neutralizing epigenomes in neurodevelopmental disorders

中和神经发育障碍中的表观基因组

基本信息

批准号：
9085410
负责人：
Shigeki Iwase
金额：
$ 32.71万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9085410
关键词：
Accounting Address Aggressive behavior Behavioral Brain ChIP-seq Chemicals Chromatin Cognitive deficits Collaborations Data Deposition Development Drug Targeting Ensure Enzymes Epigenetic Process Epilepsy Equilibrium Excision Foundations Gene Expression Gene Expression Profile Genes Genome Goals Growth Health Histone H3 Histones Human Human Genome In Vitro Individual Intellectual functioning disability Knock-out Knockout Mice Knowledge Laboratories Lead Learning Link Lysine Mediating Memory impairment Messenger RNA Methylation Methyltransferase Missense Mutation Modification Molecular Molecular Profiling Mus Mutation Nature Neurodevelopmental Disorder Neurons Outcome Patients Pattern Post-Transcriptional Regulation Post-Translational Protein Processing Proteins RNA Interference Regulation Reporting Research Research Personnel Role Shipping Ships Synapses Testing Therapeutic Vertebral column Work X-linked intellectual disability autism spectrum disorder base cognitive development cognitive function epigenome genome-wide histone methylation histone modification human disease improved in vivo inhibitor/antagonist innovation insight interdisciplinary approach learning ability loss of function mouse model neuron development overexpression promoter restoration small molecule inhibitor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): In neurodevelopmental disorders such as intellectual disabilities (ID) and autism spectrum disorders (ASD), a large number of mutations in more than 30 regulators of posttranslational modification on histones have recently been found. Intricate regulation of the histone modifications, therefore, appears to be essential for proper cognitive development. However, because little is known about how these mutations lead to IDs and ASDs, no rationale therapeutic options are available for the patients. The long-term research goal of my laboratory is to elucidate histone modification-mediated mechanisms underpinning normal and pathological brain development and function. Mutations in KDM5C account for at least up to 2% of X-linked ID (XLID). Patients with these mutations often show epilepsy and aggressive behaviors. We previously discovered that KDM5C encodes the first eraser enzyme for di- and trimethylated histone H3 lysine 4 (H3K4me2/3). Missense mutations associated with ID de- crease the demethylase activity, suggesting that the mutations lead to loss of function. More recently, we found that Kdm5c-deficient mice closely recapitulate behavioral abnormalities of human patients, including impaired learning ability and profound aggression. The Kdm5c-deficient mice are the first mouse model of ID, which is caused by defective "erasure" of histone modifications. Our work was the first to link the dynamic nature of his- tone methylation to human cognitive development. To be removed by KDM5C, the H3K4me marks are placed by a group of H3K4me "writer" enzymes. In humans, seven H3K4me writer enzymes are reported to place H3K4me marks, whereas six enzymes including KDM5C remove H3K4me. However, the functional relation- ships between KDM5C and any of the H3K4me writer enzymes for H3K4me are not known. The proposed study will address the fundamental question, "How and where in the genome does the balancing act between writers and erasers of histone modifications ensure cognitive development and function?" The specific goal of the proposed research is to elucidate the functional dynamics between KDM5C, an H3K4me eraser, and H3K4me writer enzymes. We will systematically identify the H3K4me writer enzymes that counteracts with KDM5C at molecular, cellular, and behavioral levels. Completion of the work will likely provide a potential drug target of ID. Because virtually all histone modifications are dynamically placed and erased, our approach might be broadly applicable to many other human diseases that involve dysregulation of histone modification. Importantly, the research will be the first to reveal interplay between specific epigenetic writers and erasers during neuronal development.

描述（由应用程序提供）：在神经发育障碍（例如智力障碍（ID）和自闭症谱系障碍（ASD））中，最近发现了30多个超过30种对组蛋白翻译后修饰的调节剂中的大量突变。因此，对组蛋白修饰的复杂调节似乎对于适当的认知发展至关重要。但是，对于这些突变如何导致ID和ASD的知识知之甚少，患者没有理由治疗选择。我实验室的长期研究目标是阐明基于正常和病理大脑发育和功能的组蛋白修饰介导的机制。 KDM5C中的突变至少占X连锁ID（XLID）的2％。这些突变的患者经常表现出癫痫和侵略性行为。我们以前发现KDM5C编码第一种橡皮酶和三甲基化组蛋白H3赖氨酸4（H3K4ME2/3）。与ID脱落相关的错义突变，脱甲基酶活性，表明突变导致功能丧失。最近，我们发现KDM5C缺陷小鼠密切概括了人类患者的行为异常，包括学习能力受损和深刻的侵略。 KDM5C缺陷小鼠是ID的第一个小鼠模型，它是由组蛋白修饰的“擦除”缺陷引起的。我们的工作是第一个将his-iton甲基化的动态性质与人类认知发展联系起来的工作。要通过KDM5C去除，H3K4ME标记由一组H3K4ME“作者”酶放置。在人类中，据报道7种H3K4ME作者酶放置H3K4ME标记，而包括KDM5C在内的六种酶删除了H3K4me。但是，尚不清楚KDM5C与任何H3K4ME作者酶之间的功能关系 - 尚不清楚。拟议的研究将解决一个基本问题：“基因组如何以及在何处平衡作者和橡皮图之间的组蛋白修饰的作用确保认知发展和功能？”拟议的研究的具体目标是阐明KDM5C，H3K4ME橡皮擦和H3K4ME作者酶之间的功能动力学。我们将系统地确定在分子，细胞和行为水平上与KDM5C抵消的H3K4ME作者酶。工作的完成可能会提供ID的潜在药物目标。由于实际上所有的Hisstone修饰都是动态放置和擦除的，因此我们的方法可能广泛地适用于许多其他涉及组蛋白修饰失调的人类疾病。重要的是，这项研究将是第一个在神经元发育过程中揭示特定表观遗传作者和橡皮擦之间相互作用的一项。