PUS7 pseudouridylation of 7SK orchestrates human somatic cell reprogramming into iPS cells

Abstract Reprogramming human somatic cells into induced pluripotent stem cells (iPS cells) provides huge potential for regenerative medicine but its molecular regulation remains incompletely understood. In this study, we identify PUS7 as an RNA modification checkpoint that promotes acquisition of pluripotency. PUS7 loss markedly impairs reprogramming, whereas its overexpression accelerates reprogramming efficiency and kinetics. Mechanistically, PUS7 pseudouridylates U250 of the chromatin-associated noncoding RNA 7SK, enhancing its interaction with the BRG/BRM-associated factor (BAF) complex. Loss of this modification disrupts 7SK–BAF association, reduces BAF chromatin occupancy and decreases global chromatin accessibility. We further establish PSKM (PUS7, SOX2, KLF4, MYC) reprogramming, which generates iPS cells with faithful imprinting, robust lineage potential and improved developmental fidelity. PSKM-iPS cells differentiate efficiently toward neural and hematopoietic lineages and undergo gastrulation-like morphogenesis. These findings link 7SK pseudouridylation to chromatin remodeling and establish PSKM as a framework for generating high-quality human iPS cells for modeling and regenerative medicine.