The mechanistic basis of human epigenome establishement

在这项研究中，我们试图确定决定人类细胞DNA甲基化模式的因素，其长期目标是阐明调节基因表达的机制。首先，基于对免疫缺陷综合征伴随DNA低甲基化的某些DNA序列的研究，我们发现ZBTB24蛋白是一种新的甲基化模式决定因素。在小鼠中进行的基因敲除研究证实，它确实是一个调节DNA甲基化的因素。其次，基于对人类和黑猩猩甲基化模式的比较研究，我们确定了转录因子CTCF蛋白及其靶序列是甲基化决定因素。破坏CTCF结合的物种特异性序列变化与超甲基化相关。最后，我们确定了串联重复序列中的CpG二核苷酸密度是另一个决定因素。我们的研究结果为研究甲基化在进化、变异和癌症等疾病中的作用提供了基础。

In tis study, we tried to identify factors that determine DNA methylation patterns of human cells, with a long-term goal of clarifying mechanisms regulating gene expression. First, we identified ZBTB24 protein as a novel methylation pattern determinant, based on the study of an immune-deficiency syndrome accompanied by DNA hypomethylation at certain DNA sequences. A gene knockout study in mice confirmed that it is indeed a factor regulating DNA methylation. Second, based on the comparative study of methylation patterns between human and chimpanzee, we identified CTCF protein, a transcription factor, and its target sequence as methylation determinants. Species-specific sequence changes that disrupted CTCF binding were correlated with hypermethylation. Lastly, we identified CpG dinucleotide density in tandem repetitive sequences as another determinant. Our results provide a basis to study the roles of methylation in evolution, variability and disease such as cancer.