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

项目摘要 表观遗传因子是编码蛋白质的基因，这些蛋白质可以影响DNA的空间组织和 基因区域对转录机制的可及性，从而调节细胞类型的特定转录。 在患有儿科综合征的儿童中，已建立的表观基因的致病突变高度丰富， 通常有影响多个器官系统的症状，如大脑、心脏、胃肠道、骨骼、眼睛 还有肾脏。智力残疾、发育迟缓、自闭症、腹泻和 先天性心脏病的严重程度因人而异。这些症状在早期的发病 童年表明，许多这些表观遗传因素对早期发育过程和细胞- 命运的转变。尽管我们改进了外显子组测序的诊断能力，但 表观遗传因子突变及其干扰哺乳动物发育的直接机制 目前仍不清楚这些过程。组蛋白乙酰转移酶(HATS)是使赖氨酸(K)残基乙酰化的基因 并代表了一种控制DNA对转录机制的可及性的共同机制。在这里，我们 研究两个HAT中的蛋白质截断变体：赖氨酸(K)、乙酰转移酶6A和6B(KAT6A和KAT6B)， 导致Arboleda-Tham综合征(ARTHS)和生殖器综合征(GPS)或比如说-Barber-Biesecker- 分别为青年综合征(SBBYS)。我们的目标是开发和验证转基因小鼠模型 这些基因的患者特异性突变以确定这些表观遗传因子在细胞中的不同作用 开发过程中的规范驱动了不同的症状。

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.