PRAMEL7 and CUL2 decrease NuRD stability to establish ground-state pluripotency

• Published in: EMBO reports 2024-03, Vol.25 (3), p.1453-1468
• Main Authors: Rupasinghe, Meneka, Bersaglieri, Cristiana, Leslie Pedrioli, Deena M, Pedrioli, Patrick GA, Panatta, Martina, Hottiger, Michael O, Cinelli, Paolo, Santoro, Raffaella
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Cell Differentiation - genetics; Chromatin - metabolism; EMBO09; EMBO31; EMBO34; Embryonic Stem Cells - metabolism; Life Sciences; Pluripotent Stem Cells - metabolism; Transcriptome
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00083-z

Pluripotency is established in E4.5 preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of pluripotency, however, their gene expression signature only partially resembles that 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 inducing a 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 regulators of repressive chromatin, including the NuRD complex, for proteasomal degradation. 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. Synopsis PRAMEL7 reprograms ESC to ground-state pluripotency by recruiting CUL2 to chromatin and targeting chromatin regulators for proteasomal degradation. This leads to a gene expression signature close to developmental ground-state, linking proteasome degradation pathways to ground-state gene expression. PRAMEL7 associates with and recruits CULLIN2 to chromatin. PRAMEL7-CULLIN2 interaction is required to establish gene expression signature close to developmental ground-state. PRAMEL7 targets regulators of repressive chromatin, including the NuRD complex, for proteasomal degradation in a CULLIN2-dependent manner. PRAMEL7 antagonizes NuRD-mediated repression by decreasing NuRD stability and promoter association in a CUL2-dependent manner. PRAMEL7 reprograms ESC to ground-state pluripotency by recruiting CUL2 to chromatin and targeting chromatin regulators for proteasomal degradation. This leads to a gene expression signature close to developmental ground-state, linking proteasome degradation pathways to ground-state gene expression.