Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Department of Molecular and Cellular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Cell Rep. 2018 Aug 7;24(6):1496-1511.e8. doi: 10.1016/j.celrep.2018.07.026.
During somatic reprogramming, Yamanaka's pioneer factors regulate a complex sequence of molecular events leading to the activation of a network of pluripotency factors, ultimately resulting in the acquisition and maintenance of a pluripotent state. Here, we show that, contrary to the pluripotency factors studied so far, overexpression of Mybl2 inhibits somatic reprogramming. Our results demonstrate that Mybl2 levels are crucial to the dynamics of the reprogramming process. Mybl2 overexpression changes chromatin conformation, affecting the accessibility of pioneer factors to the chromatin and promoting accessibility for early immediate response genes known to be reprogramming blockers. These changes in the chromatin landscape ultimately lead to a deregulation of key genes that are important for the mesenchymal-to-epithelial transition. This work defines Mybl2 level as a gatekeeper for the initiation of reprogramming, providing further insights into the tight regulation and required coordination of molecular events that are necessary for changes in cell fate identity during the reprogramming process.
在体细胞重编程过程中，山中伸弥的先驱因子调节着一系列复杂的分子事件，导致多能性因子网络的激活，最终获得并维持多能状态。在这里，我们表明，与迄今为止研究的多能性因子相反，Mybl2 的过表达抑制体细胞重编程。我们的结果表明，Mybl2 水平对于重编程过程的动力学至关重要。Mybl2 过表达改变染色质构象，影响先驱因子与染色质的可及性，并促进早期瞬时反应基因的可及性，这些基因已知是重编程抑制剂。染色质景观的这些变化最终导致关键基因的失调，这些基因对于间充质到上皮的转变很重要。这项工作将 Mybl2 水平定义为重编程启动的门控因子，为进一步了解在重编程过程中细胞命运身份变化所需的分子事件的紧密调控和所需协调提供了深入的见解。
