Nucleolar protein PEXF controls ribosomal RNA synthesis and pluripotency exit

Maintenance and exit from pluripotency of embryonic stem cells (ESCs) are controlled by highly coordinated processes of protein synthesis and ribosome biogenesis (RiBi). ESCs are characterized by low rates of global protein synthesis and high levels of RiBi. Transient reduction of RiBi is a characteristic molecular event during the exit from pluripotency, of which the regulatory mechanism is unclear. Here, we identify that a previously uncharacterized nucleolar protein, pluripotency exit factor (PEXF), encoded by long noncoding RNA LINC00472, plays a role in the transient reduction of RiBi. PEXF dissociates RNA polymerase I from the rDNA through interaction with the rDNA promoter region in a liquid-liquid phase separation-dependent manner, therefore inhibiting the production of pre-ribosomal RNA, a key component of ribosomes. This finding reveals a potential mechanism of exit from pluripotency gated by ribosome levels in human ESCs.