Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Sci Rep. 2018 Jul 4;8(1):10138. doi: 10.1038/s41598-018-28356-3.
DNA methylation plays a key role in X-chromosome inactivation (XCI), a process that achieves dosage compensation for X-encoded gene products between mammalian female and male cells. However, differential sex chromosome dosage complicates genome-wide epigenomic assessments, and the X chromosome is frequently excluded from female-to-male comparative analyses. Using the X chromosome in the sexually dimorphic mouse liver as a model, we provide a general framework for comparing base-resolution DNA methylation patterns across samples that have different chromosome numbers and ask at a systematic level if predictions by historical analyses of X-linked DNA methylation hold true at a base-resolution chromosome-wide level. We demonstrate that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI. While our observations concur with longstanding observations of XCI at promoter-proximal CpG islands, we provide evidence that sex-specific DNA methylation differences are not limited to CpG island boundaries. Moreover, these data support a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation. Further, we validate an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver. Our analyses provide insight into underlying methylation patterns that should be considered when assessing sex differences in genome-wide methylation analyses.
DNA 甲基化在 X 染色体失活（XCI）中起着关键作用，这是一种在哺乳动物雌性和雄性细胞之间实现 X 编码基因产物剂量补偿的过程。然而，性染色体剂量的差异使全基因组表观基因组评估变得复杂，并且 X 染色体经常从雌性到雄性的比较分析中排除。我们使用在性别二态性小鼠肝脏中的 X 染色体作为模型，提供了一个用于比较具有不同染色体数的样本中碱基分辨率 DNA 甲基化模式的通用框架，并在系统水平上询问历史上分析 X 连锁 DNA 甲基化的预测是否在碱基分辨率全染色体水平上成立。我们证明 X 染色体上的性别特异性甲基化模式在很大程度上反映了 XCI 的影响。虽然我们的观察结果与启动子近端 CpG 岛处 XCI 的长期观察结果一致，但我们提供的证据表明，性别特异性 DNA 甲基化差异不仅限于 CpG 岛边界。此外，这些数据支持一种模型，即维持非活性状态的 CpG 岛不需要完全区域甲基化。此外，我们在逃避 XCI 的小鼠肝脏基因中验证了一个内含子非 CpG 甲基化特征。我们的分析提供了在评估全基因组甲基化分析中的性别差异时应考虑的潜在甲基化模式的见解。
