Epigenetic and transcriptional consequences of Intellectual Disability-associated mutations in the histone lysine demethylase KDM5.

组蛋白赖氨酸去甲基化酶 KDM5 中与智力障碍相关的突变的表观遗传和转录后果。

• 批准号: 10625335
• 负责人: Matanel Yheskel
• 金额: $ 4.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2026-05-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625335
• 关键词: Ablation; Address; Adult; Affect; Age; Binding; Biological Assay; Biology; Biotin; Brain; Caregivers; Cognition; Cognitive; Consensus Sequence; DNA; Data; Defect; Desire for food; Development; Disease; Down-Regulation; Drosophila genus; Drosophila melanogaster; Education; Epigenetic Process; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Histones; Human; Impaired cognition; Individual; Intellectual functioning disability; Knockout Mice; Label; Lead; Learning; Link; Lysine; Maintenance; Mass Spectrum Analysis; Memory; Methylation; Modeling; Molecular; Mutation; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Orthologous Gene; Pathway interactions; Patients; Phenotype; Population; Process; Protein Family; Proteins; Publishing; Puromycin; Radial; Ribosomal Proteins; Role; Testing; Therapeutic; Tissues; Translations; X-linked intellectual disability; chromatin immunoprecipitation; chromatin modification; clinically relevant; cognitive function; demethylation; exome sequencing; fly; genome-wide; histone demethylase; histone modification; improved; in vivo; insight; knock-down; long term memory; loss of function; mutant; neuron development; paralogous gene; promoter; protein protein interaction; recruit; social; therapeutic target; transcriptome sequencing

ABSTRACT Intellectual disabilities (ID) are a group of neurodevelopmental disorders characterized by difficulties in memory, cognition, and adaptive function by the age of 18. Whole exome sequencing from patients with ID reveals mutations in the genes encoding KDM5A, B, and C. One to three percent of X-linked ID (X-LID) is attributed to the highly neuronally expressed paralog KDM5C. KDM5 proteins are best known for their enzymatic demethylation of H3 that is tri-methylated on lysine 4 (H3K4me3), a chromatin modification associated with transcriptionally active promoters. Though Kdm5c knockout mice show cognitive phenotypes, no clinically relevant pathways have been identified and the mechanism by which KDM5 regulates transcription is still unclear. Drosophila possess a single, well conserved ortholog of KDM5 in which we can model patient- associated ID mutations to understand their effects on neuronal development. A previous study from our lab modeling ID mutations in Drosophila reveals a reduction in expression of ribosomal protein genes (RPG), total protein translation, and defects in both short and long-term memory. De novo translation is necessary for memory formation and is found to be altered in several ID disorders. Importantly, restoring translational defects are an emerging and potentially therapeutic means to improve the cognitive function of individuals with ID. Hindering the development of any therapies is a lack of understanding of how KDM5 functions molecularly to regulate the expression of RP and other genes, the extent to which this requires its canonical histone demethylase activity, and how KDM5 function is altered by ID-associated mutations. Here, we specifically address these key issues by systematically decoding the role of KDM5 in RPG expression by assessing promoter H3K4me3 levels, the KDM5 interactome, and how these are altered by ID mutations.

摘要 智力障碍(ID)是一组以记忆障碍为特征的神经发育障碍， 18岁前的认知和适应功能。ID患者的整个外显子组序列显示 编码KDM5A、B和C的基因突变1%到3%的X连锁ID(X-LID)被归因于 高神经元表达的Paralog KDM5C。KDM5蛋白最为人所知的是它们的酶 赖氨酸4(H3K4me3)上三甲基化的H3去甲基化，一种与 转录活性启动子。虽然Kdm5c基因敲除小鼠表现出认知表型，但在临床上没有 相关的途径已经确定，KDM5调节转录的机制仍然是 不清楚。果蝇拥有一个保守的KDM5同源基因，我们可以在其中模拟患者- 相关的ID突变，以了解它们对神经元发育的影响。我们实验室以前的一项研究 在果蝇中模拟ID突变显示核糖体蛋白基因(RPG)的表达减少，总 蛋白质翻译，以及短期和长期记忆的缺陷。从头翻译对于记忆来说是必要的 形成，并被发现在几个ID障碍中改变。重要的是，修复翻译缺陷是一种 新兴和潜在的治疗手段，以改善ID障碍患者的认知功能 任何疗法的发展都是缺乏对KDM5如何在分子上调节 RP和其他基因的表达，这需要其标准组蛋白去甲基酶活性的程度， 以及ID相关突变如何改变KDM5的功能。在这里，我们专门解决这些关键问题 通过系统地解码KDM5在RPG表达中的作用，通过评估启动子H3K4me3的水平， KDM5互动组，以及ID突变是如何改变这些的。