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

基本信息

批准号：
9334893
负责人：
Alexander Gimelbrant
金额：
$ 97.49万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
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/9334893
关键词：
Address Affect Alleles Allelic Imbalance Alpha Cell Alzheimer&apos 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 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 Genotype Heterogeneity Human 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 Reagent 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 genome-wide analysis genomic data high throughput screening human stem cells imaging approach imprint in vivo innovation innovative technologies insight lymphoblast male mutant new technology novel novel strategies personalized medicine programs protein protein interaction public health relevance response single molecule small hairpin RNA stem tool trait transcriptome sequencing

项目摘要

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）是最近发现的一种表观遗传现象，它控制超过10%的哺乳动物基因中母本和父本等位基因的相对表达。尽管 MAE 会影响雄性和雌性细胞中的基因，但随机选择活性等位基因并通过 MAE 稳定维持的方式与 X 染色体失活非常相似。当两个等位基因在功能上不同时，MAE 可以深刻影响细胞命运，导致同一个体内的两个姐妹细胞以截然相反的方式发挥作用，具体取决于该基因的正常或突变等位基因是否活跃。了解 MAE 的功能和机制应显着有助于揭示特定基因变异与多种疾病易感性之间的精确联系。受MAE影响的基因与癌症、自闭症和阿尔茨海默病等重大疾病有关，有望对生物医学的多个领域产生重大影响。然而，传统技术方法的不足阻碍了理解 MAE 机制和功能方面的进展，传统技术方法无法对固有地产生巨大细胞间变异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的情况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。结果，研究人员缺乏基础知识，甚至缺乏有效生成这些知识的工具。为此，我们开发并验证了几种规避这一障碍的开创性方法，并能够准确、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、机制和遗传学研究。我们建议使用和扩展几种新技术来直接解决有关 MAE 生物学的关键问题。我们将剖析人类细胞中多次细胞分裂中 MAE 启动、发展和稳定维持所涉及的分子机制，为靶向操纵等位基因活性打开大门。我们还建议回答以下有关 MAE 影响的基本功能问题：MAE 在生物体体内的普遍程度如何？个体之间有何差异？广泛的 MAE 会产生哪些功能性后果？该项目的成功完成将为准确解释人类正常发育和疾病背景下的基因型-表型关系提供关键知识。它还将为细胞间和个体间的变异性提供新的理解。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转化为个性化医疗背景下的诊断、预防和治疗。