Neutralizing epigenomes in neurodevelopmental disorders

 描述(申请人提供)：在智能障碍(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控因子的大量突变。因此，对组蛋白修饰的复杂调控似乎对正常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，因此没有合理的治疗方案可供患者选择。我的实验室的长期研究目标是阐明组蛋白修饰介导的机制，以支持正常和病理性的脑发育和功能。KDM5C的突变至少占X连锁ID(XLID)的2%。带有这些突变的患者通常会表现出癫痫和攻击性行为。我们先前发现KDM5C编码第一个组蛋白H3赖氨酸4(H3K4me2/3)的双甲基化和三甲基化的擦除酶。与ID相关的错义突变会降低去甲基酶的活性，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密切相关，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的小鼠模型，ID是由组蛋白修饰的缺陷“擦除”引起的。我们的工作首次将His-Tone甲基化的动态性质与人类认知发展联系起来。要被KDM5C去除，H3K4Me标记由一组H3K4Me“写入者”酶放置。据报道，在人类中，七种H3K4me写入酶可以标记H3K4me，而包括KDM5C在内的六种酶可以去除H3K4me。然而，KDM5C和H3K4me的任何H3K4me编写器酶之间的功能关系尚不清楚。这项拟议的研究将解决这样一个基本问题：“在基因组中，组蛋白修饰的编写者和擦除者之间的平衡如何以及在哪里确保认知发展和功能？”这项拟议研究的具体目标是阐明H3K4me橡皮擦KDM5C和H3K4me写入器酶之间的功能动力学。我们将在分子、细胞和行为水平上系统地鉴定与KDM5C相互作用的H3K4me编写器酶。这项工作的完成可能会为ID提供一个潜在的药物靶点。因为几乎所有的组蛋白修饰都是动态放置和擦除的，我们的方法可能广泛适用于许多其他涉及组蛋白修饰调控失调的人类疾病。重要的是，这项研究将首次揭示神经元发育过程中特定的表观遗传编写器和擦除器之间的相互作用。

 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.