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: 8929259
• 负责人: Alexander Gimelbrant
• 金额: $ 109.51万
• 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/8929259
• 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; Genetic study; Genomics; Genotype; Health; Heterogeneity; Human; Image; In Vitro; Individual; Knowledge; Lead; Link; Lymphocyte; Lymphoid Cell; Maintenance; Malignant Neoplasms; Mammals; Masks; Measurement; Measures; Mediating; 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; personalized medicine; programs; protein protein interaction; response; single molecule; small hairpin RNA; stem; tool; trait; transcriptome sequencing

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）：常染色体单等位基因表达（MAE）是最近发现的表观遗传现象，其控制超过10%的哺乳动物基因中母本和父本等位基因的相对表达。活性等位基因被随机选择然后由于MAE而稳定维持的方式非常类似于X染色体失活，尽管MAE影响男性和女性细胞中的基因。当两个等位基因在功能上不同时，MAE可以深刻地影响细胞命运，导致同一个体内的两个姐妹细胞以完全相反的方式运行，这取决于基因的正常或突变等位基因是否活跃。了解MAE的功能和机制将有助于揭示特定基因变异与多种疾病易感性之间的确切联系。 受MAE影响的基因与包括癌症、自闭症和阿尔茨海默病在内的重大疾病有关，这预示着MAE研究将对生物医学的多个领域产生重大影响。然而，在理解MAE的机制和功能方面的进展受到传统技术方法不足的阻碍，这些方法不允许系统分析固有地产生巨大细胞间变异的机制。这种表观遗传异质性掩盖了在批量分析细胞的背景下等位基因表达的变化，例如大多数全基因组和高通量研究策略。因此，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，我们已经开发并验证了几种突破这一障碍的开创性方法，并能够准确和精确地评估人体细胞和组织中的MAE。因此，我们第一次可以对MAE进行系统的功能，机制和遗传研究。 我们建议使用和扩展几种新技术，直接解决有关MAE生物学的关键问题。我们将剖析参与MAE启动，发展，并在人类细胞中的多个细胞分裂的稳定维护的分子机制，打开大门，有针对性地操纵等位基因活性。我们还建议回答以下关于MAE影响的基本功能问题：MAE在体内生物体中的流行程度如何？个体之间有何差异？广泛MAE的功能后果是什么？ 该项目的成功完成将为在人类正常发育和疾病背景下精确解释基因型-表型关系提供关键知识。它还将提供对细胞间和个体间变异性的新理解。这些见解，以及控制多个人类基因的特定等位基因活性的机制的知识，可以在个性化医疗的背景下转化为诊断，预防和治疗。