Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming.
Nisi, Paola Serena
Roamio Franklin, Valar Nila
American Association for the Advancement of Science (AAAS)
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Collier, A. J., Bendall, A., Fabian, C., Malcolm, A. A., Tilgner, K., Semprich, C. I., Wojdyla, K., et al. (2022). Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming.. Sci Adv, 8 (12) https://doi.org/10.1126/sciadv.abk0013
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.
Pluripotent Stem Cells, Humans, Cell Differentiation, Gene Expression Regulation, Polycomb Repressive Complex 1, Cellular Reprogramming
NICHD NIH HHS (R01 HD098387)
Wellcome Trust (206194)
NIGMS NIH HHS (P01 GM099134)
External DOI: https://doi.org/10.1126/sciadv.abk0013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336442
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/