Inhibition of N-myristoyltransferase in pluripotent stem cells promotes the naive state in mice and elicits trophectoderm and primitive endoderm markers in humans.

Abstract

Naive and primed states represent distinct phases of pluripotency during early embryonic development, both of which can be captured and interconverted in vitro. To understand pluripotency regulation, we performed a recessive genetic screen using homozygous mutant mouse embryonic stem cells (mESCs) and identified N-myristoyltransferase (NMT) as a novel regulator. Disruption of Nmt1 in mESCs conferred resistance to differentiation, and NMT suppression in mouse epiblast stem cells (mEpiSCs) promoted the conversion from the primed to the naive state. This effect was independent of proto-oncogene tyrosine-protein kinase Src (SRC), which is a major substrate of NMT and is known to promote mESC differentiation. In contrast, NMT suppression in naive-state human induced pluripotent stem cells (hiPSCs) partially induced naive markers but, more notably, expanded subpopulations expressing trophectoderm and primitive endoderm markers, most of which co-expressed the pluripotency marker POU5F1. These results identify NMT as a novel regulator of pluripotency, with distinct roles in mice and humans.