Promyelocytic Leukemia Protein (PML) Regulates Stem Cell Pluripotency Through Novel Sumoylation Targets

TL;DR

This paper shows how the PML protein helps maintain stem cell identity by regulating specific proteins and chemical modifications linked to pluripotency and cell division.

Contribution

The study identifies SALL1 and CDCA8 as new PML-regulated sumoylation targets crucial for embryonic stem cell maintenance.

Findings

PML depletion in ES cells leads to reduced self-renewal factors and increased differentiation markers.

PML promotes sumoylation of SALL1 and CDCA8, which are essential for maintaining stem cell pluripotency and proliferation.

SALL1 sumoylation enhances Wnt signaling, while CDCA8 sumoylation supports cell proliferation in ES cells.

Abstract

The promyelocytic leukemia protein (PML) and its associated nuclear bodies have recently emerged as critical regulators of embryonic stem (ES) cell identity. Despite their recognized importance, the complete spectrum of PML-mediated molecular events in ES cells remains unclear. In this report, we study how PML is shaping the proteomic and SUMO proteomic landscape in ES cells. Proteomic profiling of PML-depleted ES cells uncovered a downregulation of self-renewal factors and an upregulation of proteins associated with translation and proteasomal activity, reflecting a cellular transition from pluripotency to differentiation. Importantly, PML promotes the sumoylation of pluripotency-related factors, chromatin organizers, and cell cycle regulators. We identified SALL1 and CDCA8 as novel PML-directed sumoylation targets, both critical for ES cell maintenance. SALL1 sumoylation increases the activation of the Wnt pathway, contributing to its ability to inhibit ES cell differentiation. Similarly, CDCA8 sumoylation enhances its capacity to promote cell proliferation. Collectively, our findings demonstrate that PML regulates ES cell identity by modulating the abundance or sumoylation of key regulators involved in pluripotency and cell cycle progression.

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