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Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming

Authors :
Amanda J. Collier
Adam Bendall
Charlene Fabian
Andrew A. Malcolm
Katarzyna Tilgner
Claudia I. Semprich
Katarzyna Wojdyla
Paola Serena Nisi
Kamal Kishore
Valar Nila Roamio Franklin
Bahar Mirshekar-Syahkal
Clive D’Santos
Kathrin Plath
Kosuke Yusa
Peter J. Rugg-Gunn
Collier, Amanda J [0000-0003-1137-6874]
Bendall, Adam [0000-0002-6865-2625]
Malcolm, Andrew A [0000-0001-6240-7701]
Semprich, Claudia I [0000-0002-2446-9028]
Wojdyla, Katarzyna [0000-0003-4509-1818]
Kishore, Kamal [0000-0002-4650-8745]
Mirshekar-Syahkal, Bahar [0000-0002-2337-9442]
D'Santos, Clive [0000-0003-3425-7288]
Plath, Kathrin [0000-0001-7796-3372]
Yusa, Kosuke [0000-0002-3442-021X]
Rugg-Gunn, Peter J [0000-0002-9601-5949]
Apollo - University of Cambridge Repository
Source :
Science advances, vol 8, iss 12
Publication Year :
2022
Publisher :
American Association for the Advancement of Science (AAAS), 2022.

Abstract

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.

Details

Database :
OpenAIRE
Journal :
Science advances, vol 8, iss 12
Accession number :
edsair.doi.dedup.....d76944bf9fc5e5949191c7b1aa813c1d