Rupasinghe Meneka, Bersaglieri Cristiana, Leslie Pedrioli Deena M, Pedrioli Patrick Ga, Panatta Martina, Hottiger Michael O, Cinelli Paolo, Santoro Raffaella
Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057, Zurich, Switzerland.
Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, 8057, Zurich, Switzerland.
EMBO Rep. 2024 Mar;25(3):1453-1468. doi: 10.1038/s44319-024-00083-z. Epub 2024 Feb 8.
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.
多能性在胚胎植入前E4.5期的上胚层中建立。胚胎干细胞（ESC）代表了多能性的永生化，然而，它们的基因表达特征仅部分类似于发育基态的特征。诱导PRAMEL7表达，PRAMEL7是一种在原始内胚层中高表达但在胚胎干细胞中低表达的蛋白质，通过诱导接近发育基态的基因表达特征，将发育程度较高的胚胎干细胞+血清重编程为基态多能性。然而，PRAMEL7如何重编程基因表达仍不清楚。在这里，我们表明PRAMEL7与Cullin2（CUL2）相互作用，这种相互作用是建立基态基因表达所必需的。PRAMEL7将CUL2招募到染色质上，并靶向抑制性染色质的调节因子，包括核小体重塑去乙酰化酶（NuRD）复合物，进行蛋白酶体降解。PRAMEL7通过以CUL2依赖的方式降低NuRD的稳定性和启动子结合，拮抗NuRD介导的对多能性相关基因的抑制作用。我们的数据将蛋白酶体降解途径与基态基因表达联系起来，为生成体外模型以重现体内基态多能性提供了见解。
