Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
Cell. 2013 Feb 28;152(5):1037-50. doi: 10.1016/j.cell.2013.02.006.
Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here, we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, whereas ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a, or p21, indicating that PHF20 is required for reprogramming. Our findings demonstrate, to the best of our knowledge, a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.
虽然体细胞重编程产生诱导多能干细胞（iPSCs）与深刻的表观遗传变化相关，但表观遗传因子在这个过程中的作用和机制仍知之甚少。在这里，我们鉴定出 Jmjd3 是重编程的一个强有力的负调控因子。Jmjd3 缺陷的 MEF 产生的 iPSC 集落明显多于野生型细胞，而 Jmjd3 的异位表达则显著抑制了重编程。我们表明，Jmjd3 的抑制作用是通过组蛋白去甲基化酶依赖和非依赖途径产生的。后者途径涉及 Jmjd3 通过招募 E3 连接酶 Trim26 靶向 PHF20 进行泛素化和降解。重要的是，即使敲低 Jmjd3、Ink4a 或 p21，PHF20 缺陷的 MEF 也不能转化为完全重编程的 iPSC，表明 PHF20 是重编程所必需的。我们的研究结果表明，Jmjd3 在细胞重编程中具有以前未被认识到的作用，并为 Jmjd3-PHF20 轴控制这一过程的机制提供了分子见解。
