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

逆转录转座子是人类基因组表观遗传变异的主要来源

• 批准号: 7939210
• 负责人: JOOMYEONG KIM
• 金额: $ 43.61万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939210
• 关键词: Adult; Animals; Betaine; Biochemical Reaction; Bioinformatics; Biological Markers; Choline; Chronic Disease; DNA; DNA Methylation; Detection; Development; Disease susceptibility; Ectopic Expression; Elements; Environment; Environmental Exposure; Epidemiologic Studies; Epigenetic Process; Folic Acid; Genes; Genome; Genotype; Human; Human Genome; Inbred Strain; Individual; Intracisternal A-Particle Elements; Life; Mediating; Methylation; Modification; Molecular; Mus; Mutant Strains Mice; Nature; Phenotype; Pilot Projects; Population; Preventive; Repetitive Sequence; Retroelements; Retrotransposon; Series; Source; Staging; Testing; Transcript; Variant; Vitamin B 12; base; environmental intervention; epigenetic variation; flexibility; functional outcomes; human disease; mammalian genome; mouse genome; mutant; outcome forecast; promoter; public health relevance; transposon/insertion element

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.

描述(由申请人提供)：表观遗传修饰是决定个体与基因和环境的表型的主要因素。具有相同序列的单个人类基因组可以衍生出表观遗传修饰基因组的几个不同版本，表观基因组是人类健康生活和疾病易感性的个体间差异的原因。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因素。然而，环境暴露可能导致的表观遗传变异和随后的功能结果的分子基础在很大程度上是未知的。因此，作为挑战这些问题的第一步，该项目建议识别和表征一种类型的移动DNA元件对表观遗传变异的潜在贡献。根据对两种突变小鼠的研究结果，存活的黄色刺鼠(Avy)和Axin融合的KINKY(Axinfu)是一种重复元件，反转录转座子，在其DNA甲基化水平和相关表型上显示出不寻常的个体间差异。这促使我们从人类和小鼠基因组中鉴定出具有相似特征的反转录转座子。初步分析表明，大约3%的人类和老鼠的整个转录本可能是由反转录转座子驱动的，其中一些逆转录元件可能与老鼠的两个座位具有相似的特征：不同水平的DNA甲基化，以及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不稳定且对环境暴露敏感的主要DNA元件之一，其中一些已识别的反转录转座子可能导致人类表观基因组的变异。这些假说将以以下目的进行检验：1)根据表观遗传变异和功能结果对已识别的反转录转座子驱动的转录本进行表征，以及2)证明已识别的反转录转座子对环境干预的表观遗传亚稳定性。来自本项目的信息将非常有助于我们理解在人类群体中观察到的表观遗传变异和相关的表型差异。 公共卫生相关性：表观遗传变异导致了在不同人群中经常观察到的许多疾病易感性。该项目旨在鉴定和鉴定哺乳动物中的一种重复DNA元件，反转录转座子，它是人类和其他哺乳动物基因组表观遗传变异的主要来源。