Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Nat Commun. 2022 Jan 10;13(1):142. doi: 10.1038/s41467-021-27719-1.
The establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation.
胚胎发育过程中细胞身份的建立涉及特定基因表达程序的激活，并由包括 DNA 甲基化和组蛋白翻译后修饰在内的表观遗传因素支持。四链体是一种由 4 个链组成的 DNA 二级结构 (G4s)，它与转录调控和癌症有关。在这里，我们表明 G4 是与细胞分化相关的关键基因组结构特征。我们发现 G4 在人类胚胎干细胞中高度丰富，并在谱系特化过程中丢失。G4 广泛存在于增强子和启动子中。在胚胎和下游谱系之间共有的 G4 与参与基本细胞功能的基因的转录稳定以及组蛋白翻译后修饰景观的转变紧密相关。此外，稳定 G4 的小分子的应用会导致干细胞分化延迟，使细胞保持更类似多能的状态。总的来说，我们的数据强调了 G4 作为与干细胞多能性和分化相关的重要表观遗传特征。
