Genome-methylome Interactions

描述（由申请人提供）：DNA甲基化代表了人类基因组活性表观遗传调控的一个重要层面。众所周知，在人类个体和群体之间存在着大量的遗传变异。这种遗传变异导致相同细胞类型或组织的不同个体之间基因表达的差异。越来越多的证据表明，包括甲基组在内的表观基因组也因人而异。这种变异被认为在多种表型的个体变异中发挥功能作用，包括许多人类疾病。然而，详细的机制和表观基因组在多大程度上被遗传多态性的集合个体化，仍然很少被研究。我们将全面表征遗传多态性对个体人类甲基组的影响。本研究的最终目标是了解DNA甲基化如何沿着单个人类染色体组织，这种局部或远程组织如何与功能相关，以及遗传变异如何影响DNA甲基化的功能组织。具体目标是：(1)通过实验构建全阶段的人类二倍体基因组，作为连接DNA甲基化的短距离和长距离顺式调控因子的基础，并将甲基化与蛋白质顺式调控因子的结合以及基因表达联系起来。(2)结合mQTL关联图谱和等位基因特异性甲基化分析，定位DNA甲基化顺式调控变异。本研究将提供一种构建分阶段二倍体甲基组的方法和研究DNA甲基组远程遗传调控的分析框架。我们将在本研究中使用的HapMap样本中确定一系列顺式调控变异。实验和分析框架将适用于各种其他表观遗传修饰的遗传效应的研究。

DESCRIPTION (provided by applicant): DNA methylation represents an important layer of epigenetic regulation on the activity of the human genome. It is well known that there is a tremendous amount of genetic variation among human individuals and populations. Such genetic variation leads to the variation of gene expression among different individuals for the same cell types or tissues. Accumulating evidence suggests that the epigenome, including methylome, also varies from one individual to another. Such variation is believed to play functional roles in the individual variation of a variety of phenotypes, including many human diseases. Yet the detailed mechanisms and the extent to which the epigenome is individualized by the ensemble of genetic polymorphisms remains barely investigated. We will comprehensively characterize the effects of genetic polymorphisms on the individual human methylomes. The ultimate goal of this study is to understand how DNA methylation is organized along single human chromosomes, how do such local or long-range organizations relate to the functions, and how do genetic variations affect the functional organization of DNA methylation. The specific aims are: (1) Experimentally construction of fully phased diploid human genomes, which will serve as a chassis to connect short and long range cis-regulators of DNA methylation, and to link methylation to the binding of protein cis-regulators as well as gene expression. (2) Mapping cis-regulatory variants for DNA methylation by integrating mQTL associative mapping with allele-specific methylation analysis. This proposed study will produce a method for constructing phased diploid methylome and an analytic framework for studying long-range genetic regulation of the DNA methylome. We will identify a list of cis-regulatory variants in the HapMap samples used in this study. The experimental and analytical framework will be applicable to the study of the genetic effects on a variety of other epigenetic modifications. PUBLIC HEALTH RELEVANCE: Epigenetic processes modulate the packaging and function of the human genome in normal developmental processes and in many pathologic states, including human cancers and other common diseases. Disease susceptibility is modulated by both genetic and environmental factors through epigenetic changes. Investigating the effects of genetic variants on and DNA methylome will help elucidating the relative contributions of gene and environment to human diseases, and enabling the identification of more accurate biomarkers for disease prognosis and diagnosis.