B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors.
B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors.
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B1 SINE 结合 ZFP266 通过抑制重编程因子介导的染色质开放来阻碍小鼠 iPSC 的生成。
DOI：
10.1038/s41467-023-36097-9
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发表时间：
2023-01-30
影响因子：
16.6
通讯作者：
Kaji, Keisuke
中科院分区：
文献类型：
--
作者：
Kaemena, Daniel F.;Yoshihara, Masahito;Beniazza, Meryam;Ashmore, James;Zhao, Suling;Bertenstam, Marten;Olariu, Victor;Katayama, Shintaro;Okita, Keisuke;Tomlinson, Simon R.;Yusa, Kosuke;Kaji, Keisuke
诱导多能干细胞(IPSC)重编程是低效的，了解这种低效的分子机制是成功控制细胞特性的关键。在这里，我们报告了24个通过CRISPR/Cas9介导的全基因组敲除(KO)筛选确定的重新编程障碍基因。其中，预测的KRAB锌指蛋白(KRAB-ZFP)Zfp266的耗尽在几个重新编程环境中强烈而持续地促进小鼠IPSC的生成，成为最强大的障碍。我们发现ZFP266与OCT4(Pou5f1)、SOX2和KLF4等先导因子结合位点附近的短散布核素(Sine)结合，并阻碍染色质的开放。用共激活器域取代KRAB共抑制子，将ZFP266从抑制因子转化为IPSC重新编程的有效促进剂。我们认为，Sine-KRAB-ZFP相互作用是染色质可及性的关键调节因子，是有效改变细胞特性所必需的调节元件。此外，这项工作还可以作为进一步阐明阻碍重新编程的分子机制的资源。诱导多能干细胞(IPSC)重新编程的效率本来就很低。在这里，作者通过CRISPR/Cas9介导的全基因组敲除筛选确定了24个重新编程障碍基因，其中包括KRAB-ZFP Zfp266，其敲除持续增强小鼠IPSC的生成。
Induced pluripotent stem cell (iPSC) reprogramming is inefficient and understanding the molecular mechanisms underlying this inefficiency holds the key to successfully control cellular identity. Here, we report 24 reprogramming roadblock genes identified by CRISPR/Cas9-mediated genome-wide knockout (KO) screening. Of these, depletion of the predicted KRAB zinc finger protein (KRAB-ZFP) Zfp266 strongly and consistently enhances murine iPSC generation in several reprogramming settings, emerging as the most robust roadblock. We show that ZFP266 binds Short Interspersed Nuclear Elements (SINEs) adjacent to binding sites of pioneering factors, OCT4 (POU5F1), SOX2, and KLF4, and impedes chromatin opening. Replacing the KRAB co-suppressor with co-activator domains converts ZFP266 from an inhibitor to a potent facilitator of iPSC reprogramming. We propose that the SINE-KRAB-ZFP interaction is a critical regulator of chromatin accessibility at regulatory elements required for efficient cellular identity changes. In addition, this work serves as a resource to further illuminate molecular mechanisms hindering reprogramming. Induced pluripotent stem cell (iPSC) reprogramming is inherently inefficient. Here the authors identify 24 reprogramming roadblock genes through a CRISPR/Cas9-mediated genome-wide knockout screen including a KRAB-ZFP Zfp266, knockout of which consistently enhances murine iPSC generation.
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影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
10.5
作者：
Banito, Ana;Rashid, Sheikh T.;Gil, Jesus
通讯作者：
Gil, Jesus
癌基因 c-Jun 阻碍体细胞重编程。
影响因子：
21.3
作者：
Liu, Jing;Han, Qingkai;Pei, Duanqing
通讯作者：
Pei, Duanqing
影响因子：
5.9
作者：
Kim, Shin-Il;Oceguera-Yanez, Fabian;Hirohata, Ryoko;Linker, Sara;Okita, Keisuke;Yamada, Yasuhiro;Yamamoto, Takuya;Yamanaka, Shinya;Woltjen, Knut
通讯作者：
Woltjen, Knut