title: Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm.
abstract: How regulatory information is encoded in the genome is poorly understood and poses a challenge when studying biological processes. We demonstrate here that genomic redistribution of Oct4 by alternative partnering with Sox2 and Sox17 is a fundamental regulatory event of endodermal specification. We show that Sox17 partners with Oct4 and binds to a unique 'compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at 'canonical' binding sites. The distinct selection of binding sites by alternative Sox/Oct partnering is underscored by our demonstration that rationally point-mutated Sox17 partners with Oct4 on pluripotency genes earmarked by the canonical Sox/Oct motif. In an endodermal differentiation assay, we demonstrate that the compressed motif is required for proper expression of endodermal genes. Evidently, Oct4 drives alternative developmental programs by switching Sox partners that affects enhancer selection, leading to either an endodermal or pluripotent cell fate. This work provides insights in understanding cell fate transcriptional regulation by highlighting the direct link between the DNA sequence of an enhancer and a developmental outcome.
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore.
authors.forename: Irene
authors.initials: I
authors.lastname: Aksoy
authors.forename: Ralf
authors.initials: R
authors.lastname: Jauch
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Chen
authors.forename: Mateusz
authors.initials: M
authors.lastname: Dyla
authors.forename: Ushashree
authors.initials: U
authors.lastname: Divakar
authors.forename: Gireesh K
authors.initials: GK
authors.lastname: Bogu
authors.forename: Roy
authors.initials: R
authors.lastname: Teo
authors.forename: Calista Keow
authors.initials: CK
authors.lastname: Leng Ng
authors.forename: Wishva
authors.initials: W
authors.lastname: Herath
authors.forename: Sun
authors.initials: S
authors.lastname: Lili
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hutchins
authors.forename: Paul
authors.initials: P
authors.lastname: Robson
authors.forename: Prasanna R
authors.initials: PR
authors.lastname: Kolatkar
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D004707:Endoderm / Q000166:cytology / Q000196:embryology*; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D024002:HMGB Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C527783:Sox2 protein, mouse