Retrotransposon as a major source to epigenetic variations in the human genome

描述（由申请人提供）：表观遗传修饰是决定基因型和环境个体表型的主要因素。具有相同序列的单个人类基因组可以衍生出几种不同版本的表观遗传修饰基因组，表观基因组，其负责人类健康生活和疾病易感性的个体间差异。最近的研究表明，环境暴露可能是这些表观遗传变异的重要贡献者。然而，表观遗传变异的分子基础和随后可能由环境暴露引起的功能结果在很大程度上是未知的。因此，作为挑战这些问题的第一步，本项目提出识别和表征一种类型的移动的DNA元件对表观遗传变异的潜在贡献。根据对两种突变小鼠，活的黄色琼脂糖（Avy）和轴融合扭结（Axinfu）的研究结果，一种类型的重复元件，反转录转座子，在其DNA甲基化水平和相关表型中显示出不寻常的个体间变异。这促使我们从人类和小鼠基因组中识别具有相似特征的逆转录转座子。初步分析显示，人类和小鼠的整个转录组中约有3%可能是由逆转录转座子驱动的，并且这些逆转录元件中的一些可能具有与两个小鼠基因座相似的特征：DNA甲基化的可变水平和随后对附近基因的转录干扰。因此，我们假设哺乳动物反转录转座子可能是表观遗传学不稳定且易受环境暴露影响的DNA元件的主要类别之一，并且这些鉴定的反转录转座子中的一些可能有助于人类表观基因组的变异。这些假设将进行测试，具有以下目的：1）鉴定的反转录转座子驱动的转录本的表征在其表观遗传变异和功能的结果，和2）对环境干预的鉴定的反转录转座子的表观遗传亚稳定性的证明。本项目的信息将有助于我们理解人类群体中观察到的表观遗传变异和相关表型差异。 公共卫生相关性：表观遗传变异是导致许多疾病易感性的原因，这些疾病易感性经常在不同人群中观察到。该项目旨在鉴定和表征哺乳动物重复DNA元件之一，反转录转座子，作为人类和其他哺乳动物基因组中表观遗传变异的主要来源。

DESCRIPTION (provided by applicant): Epigenetic modification is a major contributor to determining individuals' phenotype with genotype and environment. A single human genome with an identical sequence can derive several different versions of the epigenetically modified genome, epigenome, which are accountable for interindividual variations in the healthy life and disease susceptibility of humans. Recent studies have indicated that environmental exposures may be a significant contributor to these epigenetic variations. However, the molecular bases of epigenetic variations and subsequent functional outcomes that may be caused by environmental exposures are largely unknown. Thus, as an initial step challenging these questions, this project proposes to identify and characterize the potential contributions of one type of mobile DNA elements to the epigenetic variations. According to the results from the studies on two mutant mice, viable yellow agouti (Avy) and axin-fused kinky (Axinfu), one type of repetitive elements, retrotransposons, display unusual interindividual variations in their DNA methylation levels and associated phenotypes. This has prompted us to identify retrotransposons with similar features from the human and mouse genomes. Preliminary analyses revealed that about 3% of the entire transcriptomes of human and mouse may be driven by retrotransposons, and that some of these retro elements likely have similar features as the two mouse loci: variable levels of DNA methylation and subsequent transcriptional interference to nearby genes. Thus, we hypothesize that mammalian retrotransposons may be one of the major classes of DNA elements that are epigenetically labile and susceptible to environmental exposures, and that some of these identified retrotransposons may contribute to variations in the human epigenome. These hypotheses will be tested with the following aims: 1) characterization of the identified retrotransposon-driven transcripts in terms of their epigenetic variations and functional outcomes, and 2) demonstration of epigenetic metastability of the identified retrotransposons against environmental interventions. The information from the current project will be very helpful for our understanding of epigenetic variations and related phenotypic differences observed among human populations. PUBLIC HEALTH RELEVANCE: Epigenetic variations are responsible for many disease susceptibilities that are often observed among different human populations. This project aims to identify and characterize one of mammalian repetitive DNA elements, retrotransposons, as a main source to the epigenetic variations in the human and other mammalian genomes.