Neutralizing epigenomes in neurodevelopmental disorders

中和神经发育障碍中的表观基因组

• 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
• 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

 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（申请人提供）：在智力障碍（ID）和自闭症谱系障碍（ASD）等神经发育障碍中，最近发现了30多个组蛋白翻译后修饰调节因子的大量突变。因此，组蛋白修饰的复杂调节似乎对于正确的认知发展至关重要。然而，由于人们对这些突变如何导致 ID 和 ASD 知之甚少，因此没有为患者提供合理的治疗选择。我实验室的长期研究目标是阐明组蛋白修饰介导的正常和病理性大脑发育和功能的机制。 KDM5C 突变至少占 X 连锁 ID (XLID) 的 2%。携带这些突变的患者经常表现出癫痫和攻击行为。我们之前发现 KDM5C 编码二甲基化和三甲基化组蛋白 H3 赖氨酸 4 (H3K4me2/3) 的第一个擦除酶。与 ID 相关的错义突变会降低去甲基酶活性，表明这些突变会导致功能丧失。最近，我们发现 Kdm5c 缺陷小鼠与人类患者的行为异常非常相似，包括学习能力受损和严重的攻击性。 Kdm5c 缺陷小鼠是第一个 ID 小鼠模型，这是由组蛋白修饰“擦除”缺陷引起的。我们的工作首次将组蛋白甲基化的动态性质与人类认知发展联系起来。为了被 KDM5C 去除，H3K4me 标记由一组 H3K4me“写入”酶放置。据报道，在人类中，七种 H3K4me 书写酶会放置 H3K4me 标记，而包括 KDM5C 在内的六种酶会去除 H3K4me。然而，KDM5C 和 H3K4me 的任何 H3K4me 写入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：“组蛋白修饰的书写者和擦除者之间的平衡作用如何以及在基因组中的何处确保认知发展和功能？”本研究的具体目标是阐明 KDM5C、H3K4me 擦除器和 H3K4me 写入酶之间的功能动态。我们将系统地鉴定在分子、细胞和行为水平上与 KDM5C 相互作用的 H3K4me 写入酶。这项工作的完成将可能提供 ID 的潜在药物靶点。由于几乎所有组蛋白修饰都是动态放置和删除的，因此我们的方法可能广泛适用于涉及组蛋白修饰失调的许多其他人类疾病。重要的是，该研究将首次揭示神经元发育过程中特定表观遗传写入器和擦除器之间的相互作用。