Department of Surgery, University of Cambridge, Cambridge, CB2 0QQ, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
Nat Commun. 2023 Jan 25;14(1):405. doi: 10.1038/s41467-023-36116-9.
Stem cells undergo cellular division during their differentiation to produce daughter cells with a new cellular identity. However, the epigenetic events and molecular mechanisms occurring between consecutive cell divisions have been insufficiently studied due to technical limitations. Here, using the FUCCI reporter we developed a cell-cycle synchronised human pluripotent stem cell (hPSC) differentiation system for uncovering epigenome and transcriptome dynamics during the first two divisions leading to definitive endoderm. We observed that transcription of key differentiation markers occurs before cell division, while chromatin accessibility analyses revealed the early inhibition of alternative cell fates. We found that Activator protein-1 members controlled by p38/MAPK signalling are necessary for inducing endoderm while blocking cell fate shifting toward mesoderm, and that enhancers are rapidly established and decommissioned between different cell divisions. Our study has practical biomedical utility for producing hPSC-derived patient-specific cell types since p38/MAPK induction increased the differentiation efficiency of insulin-producing pancreatic beta-cells.
干细胞在分化过程中经历细胞分裂，产生具有新细胞特征的子细胞。然而，由于技术限制，连续细胞分裂之间发生的表观遗传事件和分子机制尚未得到充分研究。在这里，我们使用 FUCCI 报告基因开发了一种细胞周期同步的人多能干细胞 (hPSC) 分化系统，用于揭示导致确定性内胚层的前两次细胞分裂过程中的表观基因组和转录组动态。我们观察到关键分化标记的转录发生在细胞分裂之前，而染色质可及性分析显示早期抑制了替代细胞命运。我们发现由 p38/MAPK 信号传导控制的激活蛋白-1 成员对于诱导内胚层是必要的，同时阻止细胞命运向中胚层转移，并且增强子在不同细胞分裂之间快速建立和停用。我们的研究对于产生 hPSC 衍生的患者特异性细胞类型具有实际的生物医学效用，因为 p38/MAPK 诱导增加了产生胰岛素的胰腺β细胞的分化效率。
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