Sox2 and Klf4 as the Functional Core in Pluripotency Induction without Exogenous Oct4
Sox2 and Klf4 as the Functional Core in Pluripotency Induction without Exogenous Oct4
复制标题
Sox2 和 Klf4 作为无外源性 Oct4 多能性诱导的功能核心
DOI：
10.1016/j.celrep.2019.10.026
复制
发表时间：
2019-11-12
期刊：
影响因子：
8.8
通讯作者：
Ding, Sheng
中科院分区：
文献类型：
--
作者：
An, Zhaojun;Liu, Peng;Ding, Sheng
异位表达Oct4、Sox2、Klf4和c-Myc可以将分化的体细胞重新编程为诱导的多能干细胞(IPSCs)。多年来，10月4日一直被认为是四大因素中关键的重新编程因素核心。在这里，我们通过报告Sox2和Klf4在重新编程中的核心功能来挑战这一观点。我们发现，在没有外源Oct4的情况下，Sox2和Klf4的多顺反子表达足以诱导多能性，而Sox2和Klf4的化学计量是必不可少的。Sox2和Klf4协同结合在基因组上，导致其靶标的表观遗传重塑，包括多能性基因和多能性网络的逐渐激活。有趣的是，不同胚层来源的细胞，成纤维细胞(中胚层)和神经前体细胞(外胚层)，显示出收敛的重编程轨迹和相似的效率。这项工作证明了Sox2和Klf4在多能性诱导中的核心作用，并表明这一机制与胚层来源无关。
Ectopic expression of Oct4, Sox2, Klf4, and c-Myc can reprogram differentiated somatic cells into induced pluripotent stem cells (iPSCs). For years, Oct4 has been considered the key reprogramming factor core of the four factors. Here, we challenge this view by reporting a core function of Sox2 and Klf4 in reprogramming. We found that polycistronic expression of Sox2 and Klf4 was sufficient to induce pluripotency in the absence of exogenous Oct4, and the stoichiometry of Sox2 and Klf4 was essential. Sox2 and Klf4 cooperatively bound across the genome, leading to epigenetic remodeling of their targets, including pluripotency genes and gradual activation of the pluripotency network. Interestingly, cells of different germ layer origins, fibroblasts (mesoderm) and neural progenitor cells (ectoderm), showed convergent reprogramming trajectories and similar efficiency. This work demonstrates a core function of Sox2 and Klf4 in pluripotency induction and shows that this mechanism is independent of germ layer origin.