Dissecting out differential molecular phenotypes across Lysine(K) AcetylTransferase mutations in mouse development

剖析小鼠发育过程中赖氨酸（K）乙酰转移酶突变的差异分子表型

• 批准号: 10727966
• 负责人: Valerie A Arboleda
• 金额: $ 23.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727966
• 关键词: Acetylation; Acetyltransferase; Affect; Automobile Driving; Barbering; Brain; Cells; Child; Childhood; Chromatin; Complex; Congenital Heart Defects; DNA; Development; Developmental Delay Disorders; Developmental Process; Diarrhea; Disease; Epigenetic Process; Eye; Gastrointestinal tract structure; Genes; Genetic; Genetic Transcription; Goals; Heart; Individual; Intellectual functioning disability; Kidney; Link; Lysine; Modeling; Mutation; Organ; Pathogenicity; Patients; Protein Truncation; Proteins; Role; Severities; Specific qualifier value; Symptoms; Syndrome; System; Transferase; Transgenic Mice; Variant; associated symptom; autism spectrum disorder; body system; bone; cell type; diagnostic value; early childhood; exome sequencing; histone acetyltransferase; improved; molecular phenotype; mouse development; mouse model

PROJECT ABSTRACT Epigenetic factors are genes that encode proteins that can affect spatial organization of DNA and the accessibility of genetic regions to transcriptional machinery, thereby regulating cell-type specific transcription. Pathogenic mutations in established epigenes are highly enriched in children with pediatric syndromic disorders, often with symptoms that affect multiple organ systems, such as the brain, heart, gastrointestinal tract, bone, eye and kidneys. The associated symptoms of intellectual disability, developmental delays, autism, diarrhea and congenital heart defects vary in severity between individuals. The onset of these syndromes during early childhood suggest that many of these epigenetic factors are critical to early developmental processes and cell- fate transitions. Despite our improved diagnostic ability with exome sequencing, the mechanistic link between epigenetic factor mutations and the direct mechanisms by which they disrupt mammalian developmental processes remains unknown. Histone acetyltransferases (HATs) are genes that acetylate lysine (K) residues and represent a common mechanism for controlling DNA accessibility to the transcriptional machinery. Here, we study protein-truncating variants in two HATs: Lysine (K), Acetyl transferase 6A and 6B (KAT6A and KAT6B), which cause Arboleda-Tham Syndrome (ARTHS) and Genitopatellar Syndrome (GPS) or Say-Barber-Biesecker- Young Syndrome (SBBYS), respectively. Our goal is to develop and validate transgenic mouse models harboring patient-specific mutations in these genes to establish the differential roles of these epigenetic factors on cell specification during development driving the distinct syndromes.

项目摘要 表观遗传因素是编码可以影响DNA和DNA空间组织的蛋白质的基因 遗传区域对转录机械的可及性，从而调节细胞类型的特异性转录。 在儿童综合症儿童中，已建立的表观遗传学的致病突变高度富集 通常有影响多个器官系统的症状，例如大脑，心脏，胃肠道，骨，眼睛 和肾脏。智力残疾，发育延迟，自闭症，腹泻和 先天性心脏缺陷在个体之间的严重程度各不相同。这些综合症早期的发作 童年表明，这些表观遗传因素中的许多对于早期发育过程和细胞至关重要 命运过渡。尽管我们通过外显子组测序提高了诊断能力，但 表观遗传因子突变和破坏哺乳动物发育的直接机制 过程仍然未知。组蛋白乙酰转移酶（HATS）是乙酰赖氨酸（K）残基的基因 并代表控制转录机械的DNA可访问性的常见机制。在这里，我们 研究两个帽子的蛋白质截短变体：赖氨酸（K），乙酰转移酶6A和6B（Kat6a和Kat6b）， 引起Arboleda-Tham综合征（Arths）和Genitopatellar综合征（GPS）或牛barber-Biesecker- 年轻综合征（SBBY）。我们的目标是开发和验证携带的转基因鼠标模型 这些基因中的患者特异性突变，以在细胞上建立这些表观遗传因素的差异作用 开发过程中的规格驱动了不同的综合症。