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Pcbp1 blocks MEK/ERK signaling and facilitate Naïve to Primed pluripotency

ABSTRACT: Embryonic stem cells (ESCs) represent a unique cell type that is characterized by the ability to self-renew and differentiate into all types of somatic cells, as well as into germ cells. An understanding of the mechanisms which underlie their functioning is necessary for their usage in regenerative medicine. Pcbp1 is a DNA/RNA poly(C)-binding protein with a broad spectrum of functions including transcription, mRNA processing, and alternative splicing. In this study, we demonstrate that Pcbp1 blocks spontaneous ESCs differentiation towards primitive endoderm (PrE) by fine-tuning MEK/ERK signaling. Knockout of Pcbp1 leads to a specific PrE Oct4+Gata6+ population which is not receptive to differentiation signals. MEK/ERK inhibition prevents this phenotype but as our RNA-seq and Mass-spec data show, further Naïve-to-Primed transition is failed and leads to cell death, which is caused by the conflict of Primed and PrE gene expression network. Our results could explain an early lethal phenotype of Pcbp1-knockout mouse embryos and make clear the affected mechanisms. This dataset represents shotgun proteomics comparison of Mus musculus ESCs in Naïve to Primed states with or without Pcbp1 mutation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Embryonic Stem Cell

SUBMITTER: Arseniy Lobov

LAB HEAD: Alexey Tomilin

PROVIDER: PXD039287 | Pride | 2026-06-04

REPOSITORIES: Pride

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			Action	DRS
	1_E_Slot1-14_1_759.d.zip	Other
	1_E_Slot1-14_1_759_calibrated.mgf	Mgf
	1_E_Slot1-14_1_791.d.zip	Other
	1_E_Slot1-14_1_791_calibrated.mgf	Mgf
	1_N_Slot1-11_1_756.d.zip	Other

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Project description:Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3b signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre-inactivation X chromosome state, global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters.Upon withdrawal of 2i/LIF, naM-CM-/ve mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalency acquisition on lineage regulatory genes. The feasibility for establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in rodent ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation of cross-species chimaeric embryos that underwent organogenesis following microinjection of human naive iPS cells into mouse morulas. Collectively, our findings establish new avenues for regenerative medicine, patient-specific iPS cell disease modelling and the study of early human development in vitro and in vivo. Total of 12 samples of naM-CM-/ve and primed human ESC lines were analyzed for gene expression. Many of the lines analyzed are genetically matched (H9, WIBR3).

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Pcbp1 blocks MEK/ERK signaling and facilitate Naïve to Primed pluripotency

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