Mechanism and function of autosomal analog of X inactivation

X失活常染色体类似物的机制和功能

• 批准号: 8755040
• 负责人: Alexander Gimelbrant
• 金额: $ 89.53万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755040
• 关键词: Accounting; Address; Affect; Alleles; Allelic Imbalance; Alzheimer' s Disease; Area; Autistic Disorder; Binding; Biological; Biology; Blood donor; Cell Communication; Cell Fraction; Cell Lineage; Cell Surface Proteins; Cell division; Cells; Characteristics; Chromatin; Code; Collaborations; Complex; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Drug resistance; Environmental Risk Factor; Epigenetic Process; Event; Female; Gene Dosage; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Heterogeneity; Human; Image; In Vitro; Individual; Knowledge; Lead; Link; Lymphocyte; Lymphoid Cell; Maintenance; Malignant Neoplasms; Mammals; Masks; Measurement; Measures; Mediating; Medicine; Methods; Mitotic; Molecular; Organism; Pan Genus; Pathway interactions; Patients; Pattern; Penetrance; Phenotype; Population; Predisposition; Prevalence; Prevention; Property; Proxy; RNA Sequences; Reagent; Relative (related person); Research; Research Personnel; Sampling; Sister; System; Technology; Therapeutic; Time; Tissues; Translating; Translational Research; Tumorigenicity; Variant; X Inactivation; analog; base; deep sequencing; epigenetic variation; functional genomics; genetic variant; genome-wide; high throughput screening; human stem cells; imprint; in vivo; innovation; innovative technologies; insight; lymphoblast; male; mutant; new technology; novel; novel strategies; programs; protein protein interaction; public health relevance; response; single molecule; small hairpin RNA; stem; tool; trait

DESCRIPTION (provided by applicant): Autosomal monoallelic expression (MAE) is a recently discovered epigenetic phenomenon that controls the relative expression of maternal and paternal alleles in more than 10% of mammalian genes. The way the active allele is randomly chosen and then stably maintained due to MAE closely resembles X chromosome inactivation, though MAE affects genes in both male and female cells. When the two alleles are functionally distinct, MAE can profoundly affect cell fate, causing two sister cells within the sam individual to perform in diametrically opposite ways, depending on whether the normal or mutant allele of the gene is active. Understanding the function and mechanism of MAE should significantly contribute to revealing the precise link between specific gene variants and susceptibility to a variety of disorders. Genes subject to MAE are implicated in major diseases including cancer, autism, and Alzheimer's disease, promising that MAE research will have a significant impact on multiple fields of biomedicine. However, progress in understanding mechanistic and functional aspects of MAE has been hindered by the inadequacy of traditional technological approaches, which don't allow for systematic analysis of a mechanism that inherently generates enormous cell-to-cell variation. This epigenetic heterogeneity masks variation in allelic expression in contexts where cells are analyzed in bulk, such as most genome-wide and high-throughput research strategies. As a result, researchers have lacked basic knowledge or even the tools for efficiently generating this knowledge. In response, we have developed and validated several pioneering methods that circumvent this barrier, and enable accurate and precise assessment of MAE in human cells and tissues. Thus, for the first time, we can conduct systematic functional, mechanistic, and genetic studies of MAE. We propose to use and extend several novel technologies to directly address critical questions about MAE biology. We will dissect the molecular mechanisms involved in MAE initiation, development, and stable maintenance over multiple cell divisions in human cells, opening the door to targeted manipulation of allelic activity. We also propose to answer the following fundamental functional questions about effects of MAE: How prevalent is MAE in an organism in vivo? How does it vary between individuals? What are the functional consequences of widespread MAE? Successful completion of this project will provide crucial knowledge for precise interpretation of genotype- phenotype relationship in the context of human normal development and disease. It will also provide new understanding of cell-to-cell and between-individual variability. These insights, as well as knowledge of the mechanisms that control the activity of specific alleles of multiple human genes, may be translated into diagnostic, preventative, and therapeutic treatments in the context of personalized medicine.

描述（由申请人提供）：常染色体单相表达（MAE）是一种最近发现的表观遗传现象，可控制超过10％的哺乳动物基因中母体和父亲等位基因的相对表达。尽管MAE与X染色体灭活相似，但随机选择活性等位基因的方式，尽管MAE会影响男性和雌性细胞的基因。当两个等位基因在功能上不同时，MAE会深刻影响细胞的命运，从而导致SAM中的两个姐妹细胞以直径相反的方式进行，具体取决于基因的正常等位基因是活性的。了解MAE的功能和机制应显着促进特定基因变异和与多种疾病的易感性之间的精确联系。 受MAE的基因与包括癌症，自闭症和阿尔茨海默氏病在内的主要疾病有关，承诺MAE研究将对多个生物医学领域产生重大影响。但是，传统技术方法不足，理解MAE的机理和功能方面的进展受到了阻碍，这种方法不允许对固有产生巨大细胞间变化的机制进行系统分析。这种表观遗传异质性掩盖了在批量分析细胞（例如大多数全基因组和高通量研究策略）中，等位基因表达的变化。结果，研究人员缺乏基本知识，甚至缺乏有效产生这种知识的工具。 作为回应，我们开发了并验证了几种绕过这种障碍的开创性方法，并能够准确，准确地评估人类细胞和组织中的MAE。因此，我们第一次可以对MAE进行系统的功能，机械和遗传研究。 我们建议使用并扩展几种新型技术，以直接解决有关MAE生物学的关键问题。我们将剖析人类细胞中多个细胞分裂的MAE启动，发育和稳定维护所涉及的分子机制，从而打开了针对性的等位基因活性操纵的大门。我们还建议回答有关MAE影响的以下基本功能问题：MAE在体内有多流行？个人之间有何不同？广泛的MAE有什么功能后果？ 该项目的成功完成将提供至关重要的知识，以在人类正常发育和疾病的背景下精确解释基因型表型关系。它还将提供对细胞间和个体之间的新理解。这些见解以及对控制多个人类基因特定等位基因活动的机制的了解，可以在个性化医学的背景下转化为诊断，预防和治疗性治疗。