2017年8月3日,国际著名学术杂志《Cell》子刊《Stem Cell Reports》杂志在线发表了美国西奈山伊坎医学院王建龙研究组的一篇研究论文,研究报道了体细胞重编程的分子机制研究突破,研究发现转录因子Nac1参与调控体细胞重编程。中国科学院生态环境研究中心研究员Faiola为论文第一作者。

多能性干细胞能够转化为体内的任何一种类型的细胞,典型的多能性干细胞包括胚胎干细胞(ESCs)和诱导多能干细胞(iPSCs)。胚胎干细胞分离自哺乳动物胚胎早期的内细胞团,诱导多能干细胞是通过细胞核重编程,将已终末分化的、仅具有单一潜能的体细胞转变为可多向分化的、具有多能分化特性的细胞。诱导多能干细胞与胚胎干细胞具有类似的特性,可分化为三胚层,亦可产生原始生殖细胞(PGCs)。因此,诱导多能干细胞具有替代胚胎干细胞的能力,不仅可避免医学上使用胚胎干细胞存在的伦理问题,还可为细胞治疗、自体医疗、药物筛选以及毒理学研究提供有利帮助。

Nac1表达的蛋白最初发现于大鼠脑的伏核中,多种癌症细胞中也存在高表达。在胚胎干细胞中,Nac1与多种干细胞因子具有相互作用,特别是和多能性相关的Nanog,以及和已被诺贝尔奖得主Yamanaka证实的重编程因子Oct4、Sox2均具有相互作用,但这些因子间的相互作用过程及机制尚未阐明。

Faiola等证实转录因子Nac1通过调节粘附因子E-cadherin的表达,进而影响体细胞重编程过程。Nac1下调E-cadherin的阻抑基因Zeb1,直接作用于基因位点抑制转录,并间接通过影响miR200家族从而调控Zeb1的mRNA水平。

Nac1调节Zeb1和E-cadherin介导的重编程。(A):Nac1表达情况下体细胞重编程示意图;(B):Nac1缺失情况下体细胞重编程示意图。

原文摘要:

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is a long and inefficient process. A thorough understanding of the molecular mechanisms underlying reprogramming is paramount for efficient generation and safe application of iPSCs in medicine. While intensive efforts have been devoted to identifying reprogramming facilitators and barriers, a full repertoire of such factors, as well as their mechanistic actions, is poorly defined. Here, we report that NAC1, a pluripotency-associated factor and NANOG partner, is required for establishment of pluripotency during reprogramming. Mechanistically, NAC1 is essential for proper expression of E-cadherin by a dual regulatory mechanism: it facilitates NANOG binding to the E-cadherin promoter and fine-tunes its expression; most importantly, it downregulates the E-cadherin repressor ZEB1 directly via transcriptional repression and indirectly via post-transcriptional activation of the miR-200 miRNAs. Our study thus uncovers a previously unappreciated role for the pluripotency regulator NAC1 in promoting efficient somatic cell reprogramming.

©2017上海麦野生物科技有限公司版权所有,沪ICP 备15052348号 丨免责声明