Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming.
Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming.
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DOI：
10.1126/sciadv.abk0013
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发表时间：
2022-03-25
期刊：
影响因子：
13.6
通讯作者：
Rugg-Gunn PJ
中科院分区：
文献类型：
--
作者：
Collier AJ;Bendall A;Fabian C;Malcolm AA;Tilgner K;Semprich CI;Wojdyla K;Nisi PS;Kishore K;Roamio Franklin VN;Mirshekar-Syahkal B;D'Santos C;Plath K;Yusa K;Rugg-Gunn PJ
揭示在人类中建立naïve多能性的机制对于多能干细胞的未来应用至关重要，包括人类囊胚的产生。然而，通过重编程控制naïve多能性建立的调控途径在很大程度上是未知的。在这里，我们使用全基因组筛选来确定人类启动naïve多能干细胞重编程的必要调节因子以及主要障碍。我们发现，细胞状态改变所必需的因素通常不会在基因表达水平上发生变化，而是以新的功能重新定位。在机制上，我们建立了变异Polycomb复合体PRC1.3和PRDM14共同抑制发育和基因调控因子以确保naïve细胞重编程。此外，重编程障碍的小分子抑制剂改善naïve细胞重编程超出目前的方法。总的来说，这项工作定义了控制人类naïve多能性建立的原则，也为细胞状态转变过程中不稳定和重新配置细胞身份的机制提供了新的见解。全基因组功能筛选揭示了建立人类naïve多能性的新机制原理。
Uncovering the mechanisms that establish naïve pluripotency in humans is crucial for the future applications of pluripotent stem cells including the production of human blastoids. However, the regulatory pathways that control the establishment of naïve pluripotency by reprogramming are largely unknown. Here, we use genome-wide screening to identify essential regulators as well as major impediments of human primed to naïve pluripotent stem cell reprogramming. We discover that factors essential for cell state change do not typically undergo changes at the level of gene expression but rather are repurposed with new functions. Mechanistically, we establish that the variant Polycomb complex PRC1.3 and PRDM14 jointly repress developmental and gene regulatory factors to ensure naïve cell reprogramming. In addition, small-molecule inhibitors of reprogramming impediments improve naïve cell reprogramming beyond current methods. Collectively, this work defines the principles controlling the establishment of human naïve pluripotency and also provides new insights into mechanisms that destabilize and reconfigure cell identity during cell state transitions. Genome-wide functional screening reveals new mechanistic principles that establish human naïve pluripotency.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.1126/science.aal2512
发表时间：
2017-06-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Almeida M;Pintacuda G;Masui O;Koseki Y;Gdula M;Cerase A;Brown D;Mould A;Innocent C;Nakayama M;Schermelleh L;Nesterova TB;Koseki H;Brockdorff N
通讯作者：
Brockdorff N
影响因子：
5.9
作者：
Guo G;von Meyenn F;Santos F;Chen Y;Reik W;Bertone P;Smith A;Nichols J
通讯作者：
Nichols J
影响因子：
7.7
作者：
Dong, Chen;Beltcheva, Mariana;Theunissen, Thorold W.
通讯作者：
Theunissen, Thorold W.