Statistical Cancer Genomics, University College London Cancer Institute, University College London, London WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14138-43. doi: 10.1073/pnas.1307242110. Epub 2013 Aug 12.
Recently, it has been demonstrated that DNA methylation, a covalent modification of DNA that can regulate gene expression, is modified as a function of age. However, the biological and clinical significance of this age-associated epigenetic drift is unclear. To shed light on the potential biological significance, we here adopt a systems approach and study the genes undergoing age-associated changes in DNA methylation in the context of a protein interaction network, focusing on their topological properties. In contrast to what has been observed for other age-related gene classes, including longevity- and disease-associated genes, as well as genes undergoing age-associated changes in gene expression, we here demonstrate that age-associated epigenetic drift occurs preferentially in genes that occupy peripheral network positions of exceptionally low connectivity. In addition, we show that these genes synergize topologically with disease and longevity genes, forming unexpectedly large network communities. Thus, these results point toward a potentially distinct mechanistic and biological role of DNA methylation in dictating the complex aging and disease phenotypes.
最近已经证实，DNA 甲基化是一种可以调节基因表达的 DNA 共价修饰，它会随着年龄的变化而发生改变。然而，这种与年龄相关的表观遗传漂移的生物学和临床意义尚不清楚。为了揭示其潜在的生物学意义，我们在此采用系统方法，在蛋白质相互作用网络的背景下研究 DNA 甲基化中发生年龄相关变化的基因，重点研究它们的拓扑性质。与其他与年龄相关的基因类别（包括长寿和疾病相关基因以及基因表达随年龄变化的基因）不同，我们在这里证明，与年龄相关的表观遗传漂移主要发生在那些占据异常低连通性的网络边缘位置的基因中。此外，我们还表明，这些基因在拓扑上与疾病和长寿基因协同作用，形成了出乎意料的大网络社区。因此，这些结果表明，DNA 甲基化在决定复杂的衰老和疾病表型方面可能具有独特的机制和生物学作用。
