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bioRxiv · 10.1101/2022.10.10.511527

PRAMEL7/CUL2 axis regulates NuRD stability to establish ground-state pluripotency in embryonic stem cells

Rupasinghe, M.·Bersaglieri, C.·Pedrioli, D. M. L.·Pedrioli, P. G. A.·Hottiger, M. O.·Cinelli, P.·Santoro, R.
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Abstract

Pluripotency is established in E4.5 preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of pluripotency, however, they only partially resemble the gene expression signature of developmental ground-state. Induced PRAMEL7 expression, a protein highly expressed in the ICM but lowly expressed in ESCs, reprograms developmentally advanced ESC+serum into ground-state pluripotency by causing DNA hypomethylation and gene expression signature close to developmental ground-state. However, how PRAMEL7 reprograms gene expression remains elusive. Here we show that PRAMEL7 associates with Cullin2 (CUL2) and this interaction is required to establish ground-state gene expression. PRAMEL7 recruits CUL2 to chromatin and targets for proteasomal degradation regulators of repressive chromatin, including NuRD complex. PRAMEL7 antagonizes NuRD-mediated repression of genes implicated in pluripotency by decreasing NuRD stability and promoter association in a CUL2-dependent manner. Our data link proteasome degradation pathways to ground-state gene expression, offering insights to generate in vitro models to reproduce the in vivo ground-state pluripotency.

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Rupasinghe, M., Bersaglieri, C., Pedrioli, D. M. L., Pedrioli, P. G. A., Hottiger, M. O., Cinelli, P., Santoro, R.. 2022-10-10. PRAMEL7/CUL2 axis regulates NuRD stability to establish ground-state pluripotency in embryonic stem cells. https://doi.org/10.1101/2022.10.10.511527

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