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PRAMEL7 and CUL2 decrease NuRD stability to establish ground-state pluripotency
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DOI：10.1038/s44319-024-00083-z.png)
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Abstract
En 中文
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. 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.
Keywords:
PRAMEL7
Cullin 2
NuRD
UHRF1
Ground-state Pluripotency
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