Pramel7-Cul2 axis establishes ground-state gene expression in embryonic stem cells

ABSTRACT: Pluripotency is established in E4.5 preimplantation epiblast, the founder populations of the adult embryo. The establishment of in vitro models that closely resemble ground-state pluripotency represents an important opportunity to study early embryo development. Pramel7, a protein highly expressed in the inner cell mass (ICM) but expressed at low levels in embryonic stem cells (ESCs), was implicated in the establishment of ground-state pluripotency. Increasing Pramel7 expression in developmentally advanced ESC+serum causes global DNA hypomethylation and induces a gene expression signature close to developmental ground-state. However, how Pramel7 affects gene expression remains elusive. Here we show that Pramel7 associates and recruits to chromatin Cullin2 (Cul2), a component of Cullin2-RING E3 ubiquitin ligase complex that is implicated in proteasomal degradation of target substrates. Pramel7-Cul2 interaction is required for the establishment of ground-state gene expression signature. We show that Pramel7/Cul2 directly target many components of repressive chromatin, including components of the Nucleosome Remodelling and Deacetylase (NuRD) complex, for degradation. We identified a set of Pramel7-regulated genes that depend on Cul2 and associate with the NuRD component Chd4. The majority of these genes are upregulated in ESCs expressing Pramel7 and linked to pluripotency pathways. Finally, we show that Chd4 binding to these genes is impaired by Pramel7 in a Cul2-dependent manner. Our data link proteasome pathway to the establishment of ground-state gene expression, offering insights that could facilitate the establishment of in vitro models to reproduce the in vivo ground-state pluripotency.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Embryonic Stem Cell

SUBMITTER: Deena Leslie Pedrioli  

LAB HEAD: Raffaella Santoro

PROVIDER: PXD032184 | Pride | 2024-01-08

REPOSITORIES: Pride