Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Stem Cell Reports. 2021 Apr 13;16(4):899-912. doi: 10.1016/j.stemcr.2021.02.016. Epub 2021 Mar 25.
CpG islands often exhibit low DNA methylation, high histone H3 lysine 4 trimethylation, low nucleosome density, and high DNase I hypersensitivity, yet the rules by which CpG islands are sensed remain poorly understood. In this study, we first evaluated the relationships between the DNA and the chromatin properties of CpG islands in embryonic stem cells using modified bacterial artificial chromosomes. Then, using a bioinformatic approach, we identified strict CpG-island density and length thresholds in mouse embryonic stem and differentiated cells that consistently specify low DNA methylation levels. Surprisingly, the human genome exhibited a dramatically different relationship between DNA properties and DNA methylation levels of CpG islands. Further analysis allowed speculation that this difference is accommodated in part by evolutionary changes in the nucleotide composition of orthologous promoters. Thus, a change in the rules by which CpG-island properties are sensed may have co-evolved with compensatory genome adaptation events during mammalian evolution.
CpG 岛通常表现出低 DNA 甲基化、高组蛋白 H3 赖氨酸 4 三甲基化、低核小体密度和高 DNA 酶 I 超敏性，但 CpG 岛被感知的规则仍知之甚少。在这项研究中，我们首先使用改良的细菌人工染色体评估了胚胎干细胞中 CpG 岛的 DNA 和染色质特性之间的关系。然后，我们使用生物信息学方法在小鼠胚胎干细胞和分化细胞中鉴定了严格的 CpG 岛密度和长度阈值，这些阈值一致地指定了低 DNA 甲基化水平。令人惊讶的是，人类基因组中 CpG 岛的 DNA 特性与 DNA 甲基化水平之间存在显著不同的关系。进一步的分析表明，这种差异部分可以通过同源启动子核苷酸组成的进化变化来适应。因此，CpG 岛特性被感知的规则的改变可能与哺乳动物进化过程中的基因组适应事件共同进化。
