Investigating molecular mechanisms and cellular functions of genomic imprinting

研究基因组印记的分子机制和细胞功能

• 批准号: 10672309
• 负责人: Amanda Joy Whipple
• 金额: $ 39.62万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672309
• 关键词: 3-Dimensional; Alleles; Angelman Syndrome; Biological Models; Biological Process; Biology; Cell physiology; Chemicals; Chromatin; Chromatin Structure; Chromosomes; Complementary RNA; DNA; Development; Disease; Disease susceptibility; Epigenetic Process; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Genomic Imprinting; Growth; Human; Individual; Inherited; Ligation; Metabolic; Modification; Molecular; Neuronal Differentiation; Organism; Parents; Pathway interactions; Physiological; Play; Prader-Willi Syndrome; RNA; Role; Scientist; Small Nucleolar RNA; Symptoms; Tissues; Untranslated RNA; Work; cell type; experience; experimental study; gene function; imprint; neurodevelopment; offspring; parental influence; tool; transcriptomics

PROJECT SUMMARY Individuals inherit one copy of each chromosome from each parent. However, the parental genomes within offspring are not functionally equivalent due to genomic imprinting, an epigenetic phenomenon in which certain genes are expressed from only one parental copy. Imprinted genes are widely expressed during development and play important roles in growth and neurodevelopment. Genomic imprinting increases disease susceptibility: genetic disruptions in the only expressed parental copy can result in imprinted disorders with frequent metabolic and neurodevelopmental symptoms. The Whipple lab seeks to determine (i) the molecular mechanisms regulating imprinted gene expression, including cell type-specific imprinted expression, and (ii) the cellular and physiological functions of imprinted genes, with a focus on imprinted non-coding RNAs. Fundamental discoveries related to genomic imprinting is expected to inform better treatments for imprinted disorders, as previously experienced in Angelman syndrome. (i) Using neuron differentiation as a model system to understand cell type-specific imprinted expression, the Whipple lab has recently identified parent-specific chromatin structure in the Kcnk9 imprinted domain that is strengthened during differentiation. This work will be extended to comprehensively quantify differences in the 3D folding of maternal and paternal alleles across imprinted domains. Future experiments will then probe the functional relationships between epigenetic modifications, chromatin structure, and gene expression in different tissues and cell types. (ii) Regarding the function of imprinted non-coding RNAs, the lab will primarily focus the next five years on discovering the targets and functions of imprinted small nucleolar RNAs (snoRNAs). snoRNAs typically guide chemical modifications on complementary RNA targets, but the targets of imprinted snoRNAs have largely evaded scientists for the past twenty years. Moreover, loss of paternally expressed snoRNAs are a major cause of Prader-Willi syndrome. The lab is developing new transcriptomic tools to discover snoRNA:target interactions, including an optimized snoRNA-RNA chimeric ligation approach for directly sequencing snoRNA targets. These findings will then be used to better understand the cellular and physiological effects of imprinted snoRNA activity and the pathways under parental influence in offspring. Through these efforts, the Whipple lab expects to uncover principles regarding epigenetic control of gene regulation and chromatin organization that broadly apply across diverse cell types, tissues, and organisms. The lab also expects to find new non-coding RNA functions with direct implications for understanding the biological processes dysregulated in imprinted disorders.

项目摘要 个体从每个父母那里继承了每个染色体的一个拷贝。然而， 由于基因组印记，后代在功能上并不等同，基因组印记是一种表观遗传现象，其中某些 基因仅从一个亲本拷贝表达。印记基因在发育过程中广泛表达 并在生长和神经发育中发挥重要作用。基因组印记增加疾病易感性： 在唯一表达的亲本拷贝中的遗传破坏可导致印记疾病， 和神经发育症状。维普莱实验室试图确定（i）分子机制 调节印迹基因表达，包括细胞类型特异性印迹表达，和（ii）细胞和 印迹基因的生理功能，重点是印迹非编码RNA。基本发现 与基因组印迹相关的研究有望为印迹疾病提供更好的治疗方法， 安格尔曼综合征的经验。 (i)使用神经元分化作为模型系统来理解细胞类型特异性印迹表达， 维普莱实验室最近在Kcnk 9印迹结构域中鉴定了亲本特异性染色质结构， 在分化过程中加强。这项工作将被扩展到全面量化的差异，在三维 跨越印迹域的母本和父本等位基因的折叠。未来的实验将探索 表观遗传修饰，染色质结构和基因表达之间的功能关系， 组织和细胞类型。(ii)关于印迹非编码RNA的功能，实验室将主要关注 在未来五年内，发现印迹小核仁RNA（snoRNA）的目标和功能。snoRNA 通常引导互补RNA靶标上的化学修饰，但印迹snoRNA的靶标 在过去的二十年里，科学家们基本上没有发现。此外，父系表达的snoRNA的丢失是一个重要的因素。 Prader-Willi综合征的主要病因该实验室正在开发新的转录组学工具来发现snoRNA：目标 相互作用，包括用于直接测序snoRNA的优化snoRNA-RNA嵌合连接方法 目标的这些发现将被用于更好地了解印迹的细胞和生理效应。 snoRNA活性和子代中受亲本影响的途径。 通过这些努力，维普莱实验室希望揭示基因表观遗传控制的原理， 调控和染色质组织广泛适用于不同的细胞类型，组织和生物体。的 实验室还希望发现新的非编码RNA功能，这对理解生物学特性有直接意义。 在印记疾病中的过程失调。