Systematic identification of barriers to human iPSC generation.
Systematic identification of barriers to human iPSC generation.
复制标题
系统地识别人IPSC产生的障碍。
DOI：
10.1016/j.cell.2014.05.040
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发表时间：
2014-07-17
期刊：
影响因子：
64.5
通讯作者：
Ramalho-Santos M
中科院分区：
文献类型：
--
作者：
Qin H;Diaz A;Blouin L;Lebbink RJ;Patena W;Tanbun P;LeProust EM;McManus MT;Song JS;Ramalho-Santos M
将体细胞重编程为诱导多能干细胞 (iPSC) 为再生医学带来了巨大希望，但其潜在机制仍知之甚少。我们通过结合全基因组 RNAi 筛选、创新计算方法、广泛的单次命中验证以及相关途径和网络的机械剖析，报告了对人类细胞重编程的系统剖析。我们发现了新的重编程障碍，包括参与转录、染色质调控、泛素化、去磷酸化、囊泡运输和细胞粘附的基因。特定的解整合素和金属蛋白酶 (ADAM) 蛋白是重编程的抑制剂，ADAM29 的解整合素结构域对于此功能是必要且充分的。网格蛋白介导的内吞作用可以用小分子靶向，并通过正向调节 TGFβ 信号传导来对抗重编程。内吞作用或泛素化的遗传相互作用研究表明，屏障途径可以以线性、平行或前馈循环结构发挥作用，从而拮抗重编程。我们的在线资源总结了这些结果，提供了人类细胞重编程障碍的全球视角。
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) holds enormous promise for regenerative medicine, but the underlying mechanisms remain poorly understood. We report a systematic dissection of human cellular reprogramming by combining a genome-wide RNAi screen, innovative computational methods, extensive single-hit validation and mechanistic dissection of relevant pathways and networks. We identify novel reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport and cell adhesion. Specific a disintegrin and metalloproteinase (ADAM) proteins are inhibitors of reprogramming, and the disintegrin domain of ADAM29 is necessary and sufficient for this function. Clathrin-mediated endocytosis can be targeted with small molecules and opposes reprogramming by positively regulating TGFβ signaling. Genetic interaction studies of endocytosis or ubiquitination reveal that barrier pathways can act in linear, parallel or feed-forward loop architectures to antagonize reprogramming. Our online resource summarizing these results provides a global view of barriers to human cellular reprogramming.
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影响因子：
23.9
作者：
Buckley, Shannon M.;Aranda-Orgilles, Beatriz;Strikoudis, Alexandros;Apostolou, Effie;Loizou, Evangelia;Moran-Crusio, Kelly;Farnsworth, Charles L.;Koller, Antonius A.;Dasgupta, Ramanuj;Silva, Jeffrey C.;Stadtfeld, Matthias;Hochedlinger, Konrad;Chen, Emily I.;Aifantis, Iannis
通讯作者：
Aifantis, Iannis
影响因子：
11.4
作者：
Tada, M;Tada, T;Surani, MA
通讯作者：
Surani, MA
影响因子：
11.4
作者：
Persaud, Avinash;Alberts, Philipp;Rotin, Daniela
通讯作者：
Rotin, Daniela
影响因子：
2.8
作者：
Calvete, JJ;Marcinkiewicz, C;Sanz, L
通讯作者：
Sanz, L
影响因子：
11.4
作者：
Li, Zhonghan;Yang, Chao-Shun;Nakashima, Katsuhiko;Rana, Tariq M.
通讯作者：
Rana, Tariq M.