KLF17 promotes human naïve pluripotency but is not required for its establishment.

Current knowledge of the transcriptional regulation of human pluripotency is incomplete, with lack of interspecies conservation observed. Single-cell transcriptomics analysis of human embryos previously enabled us to identify transcription factors, including the zinc-finger protein KLF17, that are enriched in the human epiblast and naive human embryonic stem cells (hESCs). Here, we show that KLF17 is expressed coincident with the known pluripotency-associated factors NANOG and SOX2 across human blastocyst development. We investigate the function of KLF17 using primed and naive hESCs for gain- and loss-of-function analyses. We find that ectopic expression of KLF17 in primed hESCs is sufficient to induce a naive-like transcriptome and that KLF17 can drive transgene-mediated resetting to naive pluripotency. This implies a role for KLF17 in establishing naive pluripotency. However, CRISPR-Cas9-mediated knockout studies reveal that KLF17 is not required for naive pluripotency acquisition in vitro. Transcriptome analysis of naive hESCs identifies subtle effects on metabolism and signalling pathways following KLF17 loss of function, and possible redundancy with other KLF paralogues. Overall, we show that KLF17 is sufficient, but not necessary, for naive pluripotency under the given in vitro conditions.