Gaidatzis Dimos, Burger Lukas, Murr Rabih, Lerch Anita, Dessus-Babus Sophie, Schübeler Dirk, Stadler Michael B
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland ; Swiss Institute of Bioinformatics, Basel, Switzerland.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
PLoS Genet. 2014 Feb 13;10(2):e1004143. doi: 10.1371/journal.pgen.1004143. eCollection 2014 Feb.
For the most part metazoan genomes are highly methylated and harbor only small regions with low or absent methylation. In contrast, partially methylated domains (PMDs), recently discovered in a variety of cell lines and tissues, do not fit this paradigm as they show partial methylation for large portions (20%-40%) of the genome. While in PMDs methylation levels are reduced on average, we found that at single CpG resolution, they show extensive variability along the genome outside of CpG islands and DNase I hypersensitive sites (DHS). Methylation levels range from 0% to 100% in a roughly uniform fashion with only little similarity between neighboring CpGs. A comparison of various PMD-containing methylomes showed that these seemingly disordered states of methylation are strongly conserved across cell types for virtually every PMD. Comparative sequence analysis suggests that DNA sequence is a major determinant of these methylation states. This is further substantiated by a purely sequence based model which can predict 31% (R(2)) of the variation in methylation. The model revealed CpG density as the main driving feature promoting methylation, opposite to what has been shown for CpG islands, followed by various dinucleotides immediately flanking the CpG and a minor contribution from sequence preferences reflecting nucleosome positioning. Taken together we provide a reinterpretation for the nucleotide-specific methylation levels observed in PMDs, demonstrate their conservation across tissues and suggest that they are mainly determined by specific DNA sequence features.
在很大程度上，后生动物基因组高度甲基化，仅含有少量低甲基化或无甲基化的区域。相比之下，最近在多种细胞系和组织中发现的部分甲基化结构域（PMD）并不符合这一模式，因为它们在基因组的很大一部分（20%-40%）表现出部分甲基化。虽然在PMD中甲基化水平平均降低，但我们发现在单个CpG分辨率下，它们在CpG岛和DNase I超敏位点（DHS）之外的基因组中表现出广泛的变异性。甲基化水平以大致均匀的方式从0%到100%不等，相邻的CpG之间只有很小的相似性。对各种含有PMD的甲基化组的比较表明，这些看似无序的甲基化状态在几乎每个PMD的不同细胞类型中都高度保守。比较序列分析表明，DNA序列是这些甲基化状态的主要决定因素。一个基于纯序列的模型进一步证实了这一点，该模型可以预测甲基化变化的31%（R(2)）。该模型揭示了CpG密度是促进甲基化的主要驱动特征，这与CpG岛的情况相反，其次是紧邻CpG的各种二核苷酸，以及反映核小体定位的序列偏好的较小贡献。综上所述，我们对在PMD中观察到的核苷酸特异性甲基化水平提供了一种重新解释，证明了它们在不同组织中的保守性，并表明它们主要由特定的DNA序列特征决定。
