Neutralizing epigenomes in neurodevelopmental disorders

 描述（由申请人提供）：在神经发育障碍如智力障碍（ID）和自闭症谱系障碍（ASD）中，最近发现组蛋白翻译后修饰的30多种调节因子中存在大量突变，因此，组蛋白修饰的复杂调节似乎对正确的认知发育至关重要。然而，由于对这些突变如何导致ID和ASD知之甚少，因此患者没有合理的治疗选择。我实验室的长期研究目标是阐明组蛋白修饰介导的机制，支持正常和病理性大脑发育和功能。 KDM 5C中的突变至少占X连锁ID（XLID）的2%。具有这些突变的患者通常表现出癫痫和攻击性行为。我们先前发现KDM 5C编码第一个二甲基化和三甲基化组蛋白H3赖氨酸4（H3 K4 me 2/3）的擦除酶。与ID相关的错义突变降低脱甲基酶活性，表明突变导致功能丧失。最近，我们发现Kdm 5c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。Kdm 5c缺陷小鼠是第一个ID小鼠模型，这是由组蛋白修饰的缺陷“擦除”引起的。我们的工作是第一个将甲基化的动态性质与人类认知发展联系起来的。为了被KDM 5C去除，H3 K4 me标记被一组H3 K4 me“写入器”酶放置。在人类中，据报道有7种H3 K4 me书写酶放置H3 K4 me标记，而包括KDM 5C在内的6种酶去除H3 K4 me。然而，KDM 5C与H3 K4 me的任何H3 K4 me书写酶之间的功能关系尚不清楚。 这项拟议中的研究将解决一个基本问题，“在基因组中，组蛋白修饰的书写者和擦除者之间的平衡行为如何以及在何处确保认知发展和功能？“拟议研究的具体目标是阐明KDM 5C，H3 K4 me擦除器和H3 K4 me写入酶之间的功能动力学。我们将系统地识别在分子、细胞和行为水平上与KDM 5C相抵消的H3 K4 me书写酶。这项工作的完成可能会提供一个潜在的药物目标ID。因为几乎所有的组蛋白修饰是动态放置和删除，我们的方法可能广泛适用于许多其他人类疾病，涉及组蛋白修饰失调。重要的是，这项研究将是第一个揭示神经元发育过程中特定表观遗传作家和橡皮擦之间相互作用的研究。

 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.