H1FOO-DD promotes efficiency and uniformity in reprogramming to naive pluripotency

Heterogeneity among both primed and naive pluripotent stem cell lines remains a major unresolved problem. Here we show that expressing the maternal-specific linker histone H1FOO fused to a destabilizing domain (H1FOO-DD), together with OCT4, SOX2, KLF4, and LMYC, in human somatic cells improves the quality of reprogramming to both primed and naive pluripotency. H1FOO-DD expression was associated with altered chromatin accessibility around pluripotency genes and with suppression of the innate immune response. Notably, H1FOO-DD generates naive induced pluripotent stem cells with lower variation in transcriptome and methylome among clones and a more uniform and superior differentiation potency. Furthermore, we elucidated that upregulation of FKBP1A, driven by these five factors, plays a key role in H1FOO-DD-mediated reprogramming. [Display omitted] •H1FOO-DD improves both human primed and naive iPSC reprogramming efficiency•H1FOO-DD alters chromatin accessibility that enhances iPSC reprogramming•H1FOO-DD notably enhances the generation of higher-quality naive iPSCs•FKBP1A plays a key role in H1FOO-DD-mediated iPSC reprogramming Kunitomi et al. showed that expressing the maternal-specific linker histone H1FOO fused to a destabilizing domain (H1FOO-DD), together with OCT4, SOX2, KLF4, and LMYC, in human somatic cells, improved the quality of reprogramming to both primed and naive pluripotency. This approach enables generation of human primed and naive iPSCs that are more homogenous and have improved differentiation potential.