Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context.
Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context.
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DOI：
10.1371/journal.pgen.1000602
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Kelsey KT
中科院分区：
文献类型：
--
作者：
Christensen BC;Houseman EA;Marsit CJ;Zheng S;Wrensch MR;Wiemels JL;Nelson HH;Karagas MR;Padbury JF;Bueno R;Sugarbaker DJ;Yeh RF;Wiencke JK;Kelsey KT
基因转录的表观遗传控制对人类正常发育和细胞分化至关重要。虽然表观遗传标记如DNA甲基化的改变与癌症和许多其他人类疾病有关，但由于衰老，环境因素或先天易感性而导致的正常组织中的个体间表观遗传变异的特征很差。基因表达的可塑性、组织特异性和变异性与个体间不同的表观基因组状态有关。因此，需要基于群体的调查，以进一步了解正常个体表观基因组的基本动态。我们分析了来自10个解剖部位的217个非病理性人体组织，这些组织位于与773个基因相关的1，413个常染色体CpG位点，以研究DNA甲基化的组织特异性差异，并辨别衰老和暴露如何导致甲基化的正常变异。来自非监督建模的甲基化谱类别与年龄显著相关（P<0.0001），并且是组织来源的显著预测因子（P<0.0001）。在实体组织（n = 119）中，我们发现年龄和甲基化之间存在惊人的高度显著的CpG岛依赖性相关性; CpG岛中的基因座随着年龄的增长而获得甲基化，而不在CpG岛中的基因座随着年龄的增长而失去甲基化（P<0.001），这种模式在组织和血液来源的DNA分析中是一致的。 我们的数据清楚地表明，年龄和年龄相关的差异，组织特异性甲基化和显着的年龄相关的甲基化模式，这是CpG岛上下文依赖。这项工作为衰老和环境在癌症等疾病易感性中的作用提供了新的见解，并通过提供与年龄相关的甲基化改变导致的表观遗传失调的证据，为表观基因组学领域提供了重要信息。总的来说，我们揭示了在构建参考和疾病相关表观基因组以及解释潜在的病理学重要改变时需要考虑的关键问题。人类表观基因组中组织特异性个体间变异的原因和程度未被充分认识，因此，特征不明显。我们调查了来自10个解剖部位的200多个仔细注释的人类组织样本，在1，413个CpG上进行甲基化改变，以评估表型的性质，因此可能具有临床重要性的表观基因组改变。在组织类型中，在个体之间，我们发现甲基化的变化与衰老和吸烟等环境暴露显着相关。个体差异的年龄和年龄相关的甲基化可能显着有助于增加对几种疾病的易感性。由于NIH资助的HapMap项目对注释人类参考基因组定义正常遗传变异性做出了重要贡献，我们的工作提出了在构建参考表观基因组时需要考虑的关键问题。众所周知，了解遗传变异对了解疾病至关重要。我们的工作，以及已知的表观遗传学和遗传学的相互作用，同样清楚地表明，必须完成对表观遗传变异及其来源的更完整表征，以达到全面了解疾病的目标。进一步的研究是绝对必要的，以确定控制表观基因组变异的机制。我们已经开始为与患病组织进行比较的基本正常组织对照奠定基础，这将允许识别最关键的疾病相关改变，并为新治疗提供更强大的靶点。
Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island–dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations. The causes and extent of tissue-specific interindividual variation in human epigenomes are underappreciated and, hence, poorly characterized. We surveyed over 200 carefully annotated human tissue samples from ten anatosites at 1,413 CpGs for methylation alterations to appraise the nature of phenotypically, and hence potentially clinically important epigenomic alterations. Within tissue types, across individuals, we found variation in methylation that was significantly related to aging and environmental exposures such as tobacco smoking. Individual variation in age- and exposure-related methylation may significantly contribute to increased susceptibility to several diseases. As the NIH–funded HapMap project is critically contributing to annotating the human reference genome defining normal genetic variability, our work raises key issues to consider in the construction of reference epigenomes. It is well recognized that understanding genetic variation is essential to understanding disease. Our work, and the known interplay of epigenetics and genetics, makes it equally clear that a more complete characterization of epigenetic variation and its sources must be accomplished to reach the goal of a complete understanding of disease. Additional research is absolutely necessary to define the mechanisms controlling epigenomic variation. We have begun to lay the foundations for essential normal tissue controls for comparison to diseased tissue, which will allow the identification of the most crucial disease-related alterations and provide more robust targets for novel treatments.
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影响因子：
11.2
作者：
Christensen, Brock C.;Houseman, E. A.;Kelsey, Karl T.
通讯作者：
Kelsey, Karl T.
DOI：
10.1196/annals.1395.005
发表时间：
2007-01-01
期刊：
BIOGERONTOLOGY: MECHANISMS AND INTERVENTIONS
影响因子：
--
作者：
Fraga, Mario F.;Agrelo, Ruben;Esteller, Manel
通讯作者：
Esteller, Manel
影响因子：
9.8
作者：
DeBaun, MR;Niemitz, EL;Feinberg, AP
通讯作者：
Feinberg, AP
DOI：
10.1073/pnas.0500398102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fraga, MF;Ballestar, E;Esteller, M
通讯作者：
Esteller, M
影响因子：
120.7
作者：
Bjornsson, Hans T.;Sigurdsson, Martin I.;Feinberg, Andrew P.
通讯作者：
Feinberg, Andrew P.