Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
EMBO Rep. 2018 Apr;19(4). doi: 10.15252/embr.201744993. Epub 2018 Feb 1.
Proteins that bind to DNA depending on its methylation status play an important role in methylation-mediated regulation of gene expression. Using a variety of genomics and proteomics approaches, we identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as a reader of unmethylated DNA in mouse embryonic stem cells. ZBTB2 preferentially binds to CpG island promoters, where it acts as a transcriptional activator. The binding of ZBTB2 to its targets is direct and independent of two other zinc finger proteins, ZBTB25 and ZNF639, which we show to interact with ZBTB2. Our data suggest an anticorrelation between ZBTB2 DNA binding and DNA methylation, indicating that ZBTB2-binding dynamics are sensitive to differential DNA methylation. ZBTB2 is intricately interwoven with DNA methylation, as we find not only that its binding to DNA is methylation sensitive, but also that ZBTB2 regulates the turnover of methylated DNA In ZBTB2 knockout cells, several pluripotency factors are upregulated, inducing a delay in differentiation. We propose that ZBTB2 is a novel DNA methylation-sensitive transcription factor that regulates cellular differentiation.
依赖于 DNA 甲基化状态与 DNA 结合的蛋白质在甲基化介导的基因表达调控中发挥着重要作用。我们使用多种基因组学和蛋白质组学方法，鉴定出锌指和 BTB 结构域蛋白 2（ZBTB2）是小鼠胚胎干细胞中未甲基化 DNA 的读取蛋白。ZBTB2 优先结合 CpG 岛启动子，在那里它作为转录激活剂发挥作用。ZBTB2 与其靶标的结合是直接的，不依赖于另外两个锌指蛋白 ZBTB25 和 ZNF639，我们证明这两个蛋白与 ZBTB2 相互作用。我们的数据表明 ZBTB2 DNA 结合与 DNA 甲基化之间存在反相关，表明 ZBTB2 结合动力学对差异 DNA 甲基化敏感。ZBTB2 与 DNA 甲基化紧密交织，因为我们不仅发现其 DNA 结合对甲基化敏感，而且还发现 ZBTB2 调节甲基化 DNA 的周转。在 ZBTB2 敲除细胞中，几种多能性因子上调，导致分化延迟。我们提出 ZBTB2 是一种新型的 DNA 甲基化敏感转录因子，可调节细胞分化。
