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Highly cooperative chimeric super-SOX induces naïve pluripotency across species [ChIP-Seq]

ABSTRACT: Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission demonstrated only for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a remarkable gain-of-function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-grade OSKM iPSCs capable of supporting the development of healthy all-iPSC mice. Sox2/Oct4 dimerization emerged as the core driver of naïve pluripotency with its levels diminished upon priming. Transient overexpression of Sox2-17 and Klf4 (S*K cocktail) restored the dimerization and boosted the developmental potential of pluripotent stem cells across species, providing a universal method for naïve reset in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE247048 | GEO | 2023/11/27

REPOSITORIES: GEO

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Highly cooperative chimeric super-SOX induces naïve pluripotency across species [RRBS]

Project description:Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission demonstrated only for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a remarkable gain-of-function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-grade OSKM iPSCs capable of supporting the development of healthy all-iPSC mice. Sox2/Oct4 dimerization emerged as the core driver of naïve pluripotency with its levels diminished upon priming. Transient overexpression of Sox2-17 and Klf4 (S*K cocktail) restored the dimerization and boosted the developmental potential of pluripotent stem cells across species, providing a universal method for naïve reset in mammals.

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