Mechanism and function of autosomal analog of X inactivation

描述（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，它控制着超过10%的哺乳动物基因中母系和父系等位基因的相对表达。由于MAE的作用，活性等位基因被随机选择并稳定维持的方式与X染色体失活非常相似，尽管MAE会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表现，这取决于基因的正常等位基因还是突变等位基因是活跃的。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影响的基因与癌症、自闭症和阿尔茨海默病等重大疾病有关，MAE研究将对生物医学的多个领域产生重大影响。然而，了解MAE的机制和功能方面的进展一直受到传统技术方法不足的阻碍，传统技术方法不允许对固有的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细胞批量分析的背景下等位基因表达的差异，例如大多数全基因组和高通量研究策略。因此，研究人员缺乏基本的知识，甚至缺乏有效地产生这些知识的工具。作为回应，我们已经开发并验证了几种绕过这一障碍的开创性方法，并能够准确和精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、机制和遗传研究。我们建议使用和扩展一些新技术来直接解决MAE生物学的关键问题。我们将剖析人类细胞多次细胞分裂中MAE的起始、发展和稳定维持的分子机制，为有针对性地操纵等位基因活性打开大门。我们还建议回答以下关于MAE影响的基本功能问题：MAE在生物体体内的普遍程度如何？个体之间有什么不同？广泛性MAE的功能后果是什么？该项目的成功完成将为人类正常发育和疾病背景下基因型-表型关系的精确解释提供关键知识。它还将提供对细胞间和个体间变异性的新理解。这些见解，以及控制多种人类基因的特定等位基因活性的机制的知识，可能在个性化医疗的背景下转化为诊断，预防和治疗治疗。

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.