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Department of Molecular Mechanisms of Disease

UZH press release on the work of Santoro and Cinelli groups on stem cell pluripotency in Nature Cell Biology

Naive pluripotency is established in preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of naive pluripotency. 2i culture has optimized this state, leading to a gene signature and DNA hypomethylation closely comparable to preimplantation epiblast, the developmental ground state. The groups of Raffaella Santoro and Paolo Cinelli discovered that Pramel7 (PRAME-like 7), a protein highly expressed in the inner cell mass (ICM) but expressed at low levels in ESCs, targets for proteasomal degradation UHRF1, a key factor for DNA methylation maintenance. The results revealed that increasing Pramel7 expression in serum-cultured ESCs was sufficinet to promote a preimplantation epiblast-like gene signature, to reduce UHRF1 levels and to cause global DNA hypomethylation. Remarkably, Pramel7 is required for blastocyst formation and its forced expression locks ESCs in pluripotency. Pramel7/UHRF1 expression is mutually exclusive in ICMs whereas Pramel7-knockout embryos express high levels of UHRF1. The data reveal an as-yet-unappreciated dynamic nature of DNA methylation through proteasome pathways and offer insights that might help to improve ESC culture to reproduce in vitro the in vivo ground-state pluripotency.

Link to UZH press release