Pseudouridylation of 7SK orchestrates human somatic cell reprogramming into iPSCs [WGBS]

PUS7 deficiency reduces 7SK pseudouridylation and hinders reprogramming through disrupting the 7SK-BAF interaction, leading to reduced BAF occupancy, restricted chromatin accessibility, and impaired activation of pluripotency. Strikingly, PUS7 can functionally replace OCT4 in the Yamanaka reprogramming cocktail, enabling the generation of high-quality iPSCs using a PSKM (PUS7, SOX2, KLF4, MYC) combination. Compared to isogenic OSKM-iPSCs, PSKM-derived iPSCs exhibit reduced DNA damage, faithful imprinting, and enhanced developmental potential, closely resembling human embryonic stem cells (hESCs), thus providing a tractable in vitro model for modeling human gastrulation during the early post-implantation stage.

These findings highlight 7SK pseudouridylation by PUS7 as a central epitranscriptomic switch that regulates chromatin accessibility during human iPSC reprogramming and offer a new molecular hande to modulate reprogramming fidelity and efficiency.