Naïve pluripotency and genomic stability are coordinated in embryonic stem cells by a novel pluripotency regulator ZFP998

Efficacy and safety are key objectives in generating high-quality pluripotent stem cells (PSCs). While naïve human PSCs (hPSCs) harbor an unstable genome limiting their broad applications, mouse embryonic stem cells (mESCs) uniquely exhibit both robust pluripotency and high genomic stability. Understanding whether and how these two attributes are co-regulated in mESCs could provide critical insights for producing safe and authentic hPSCs. Here, we reveal that the coordination of naïve pluripotency and genomic stability in mESCs is governed by a novel core pluripotency regulator, ZFP998. ZFP998 binds to promoters and enhancers of key ESC-identity genes, as well as to numerous DNA damage response and repair genes, thereby regulating their expression. Depletion of Zfp998 leads to the loss of naïve pluripotency and induces severe genomic instability. Conversely, overexpression of ZFP998 is sufficient to reprogram epiblast stem cells back to a naïve pluripotent state. Importantly, ectopic expression of ZFP998 in hESCs enhances both pluripotency and genomic stability. These findings suggest that this coupled regulatory mechanism is conserved in humans and provide a promising new strategy for generating safe, naïve hPSCs.