Abstract

Changes in DNA methylation have been found to be highly correlated with aging in humans, but causes or consequences of these changes are not understood. We characterized the DNA methylomes of several hundred people in the Invecchiare in Chianti study to identify DNA sites in which percent methylation was systematically different with age. Then, we tested the hypothesis that changes of percent methylation in the same DNA sites occur longitudinally for the same DNA sites in the same subjects. We identified six differentially methylated regions in which percent methylation showed robust longitudinal changes in the same direction. We then describe functions of the genes near these differentially methylated regions and their potential relationship with aging, noting that the genes appear to regulate metabolism or cell type specificity. The nature of transcription factor binding sites in the vicinity of these differentially methylated regions suggest that these age-associated methylation changes reflect modulation of two biological mechanisms: the polycomb repressive complex 2, a protein complex that trimethylates histone H3 on lysine 27, and the transcriptional repressor CCCTC-binding factor or CTCF, both of which are regulators of chromatin architecture. These findings are consistent with the idea that changes in methylation with aging are of adaptive nature.

中文翻译：

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血液DNA甲基化和衰老：INCHIANTI研究的横断面分析和纵向验证

摘要

已经发现DNA甲基化的变化与人类衰老高度相关，但是尚不清楚这些变化的原因或后果。我们在Inanticchiare in Chianti研究中对数百人的DNA甲基化组进行了表征，以鉴定甲基化百分比随年龄系统变化的DNA位点。然后，我们测试了以下假设：同一受试者中相同DNA部位的相同DNA部位的甲基化百分比变化沿纵向发生。我们确定了六个差异甲基化区域，其中甲基化百分比在相同方向上显示出强劲的纵向变化。然后，我们描述了这些差异甲基化区域附近基因的功能及其与衰老的潜在关系，并指出这些基因似乎在调节代谢或细胞类型特异性。这些差异甲基化区域附近的转录因子结合位点的性质表明，这些与年龄相关的甲基化变化反映了两种生物学机制的调节：多梳阻抑复合物2，将赖氨酸27上的组蛋白H3三甲基化的蛋白质复合物以及转录阻遏物CCCTC结合因子或CTCF，两者都是染色质结构的调节剂。这些发现与这样的观点一致，即随着年龄的增长甲基化的变化具有适应性。以及转录阻遏物CCCTC结合因子或CTCF，它们都是染色质结构的调节剂。这些发现与这样的观点一致，即随着年龄的增长甲基化的变化具有适应性。以及转录阻遏物CCCTC结合因子或CTCF，它们都是染色质结构的调节剂。这些发现与这样的观点一致，即随着年龄的增长甲基化的变化具有适应性。