Iseki Hiroyoshi, Nakachi Yutaka, Hishida Tomoaki, Yamashita-Sugahara Yzumi, Hirasaki Masataka, Ueda Atsushi, Tanimoto Yoko, Iijima Saori, Sugiyama Fumihiro, Yagami Ken-ichi, Takahashi Satoru, Okuda Akihiko, Okazaki Yasushi
Division of Functional Genomics and Systems Medicine, Saitama Medical University, Saitama, Japan.
CREST, Japan Science and Technology Agency (JST), Saitama, Japan.
Stem Cells. 2016 Feb;34(2):322-33. doi: 10.1002/stem.2243. Epub 2015 Nov 26.
Identification of a gene set capable of driving rapid and proper reprogramming to induced pluripotent stem cells (iPSCs) is an important issue. Here we show that the efficiency and kinetics of iPSC reprogramming are dramatically improved by the combined expression of Jarid2 and genes encoding its associated proteins. We demonstrate that forced expression of JARID2 promotes iPSC reprogramming by suppressing the expression of Arf, a known reprogramming barrier, and that the N-terminal half of JARID2 is sufficient for such promotion. Moreover, JARID2 accelerated silencing of the retroviral Klf4 transgene and demethylation of the Nanog promoter, underpinning the potentiating activity of JARID2 in iPSC reprogramming. We further show that JARID2 physically interacts with ESRRB, SALL4A, and PRDM14, and that these JARID2-associated proteins synergistically and robustly facilitate iPSC reprogramming in a JARID2-dependent manner. Our findings provide an insight into the important roles of JARID2 during reprogramming and suggest that the JARID2-associated protein network contributes to overcoming reprogramming barriers.
鉴定一组能够驱动快速且正确地重编程为诱导多能干细胞（iPSC）的基因是一个重要问题。在此我们表明，通过联合表达Jarid2及其相关蛋白的编码基因，iPSC重编程的效率和动力学得到显著改善。我们证明，强制表达JARID2通过抑制已知的重编程障碍Arf的表达来促进iPSC重编程，并且JARID2的N端一半对于这种促进作用就足够了。此外，JARID2加速了逆转录病毒Klf4转基因的沉默以及Nanog启动子去甲基化，这巩固了JARID2在iPSC重编程中的增强活性。我们进一步表明，JARID2与ESRRB、SALL4A和PRDM14发生物理相互作用，并表明这些与JARID2相关的蛋白以JARID2依赖的方式协同且有力地促进iPSC重编程。我们的研究结果为JARID2在重编程过程中的重要作用提供了见解，并表明与JARID2相关的蛋白网络有助于克服重编程障碍。
