Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm

• Published in: The EMBO journal Vol. 32; no. 7; pp. 938 - 953
• Main Authors: Aksoy, Irene, Jauch, Ralf, Chen, Jiaxuan, Dyla, Mateusz, Divakar, Ushashree, Bogu, Gireesh K, Teo, Roy, Leng Ng, Calista Keow, Herath, Wishva, Lili, Sun, Hutchins, Andrew P, Robson, Paul, Kolatkar, Prasanna R, Stanton, Lawrence W
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 03.04.2013; Nature Publishing Group UK; Springer Nature B.V; EMBO Press; Nature Publishing Group
• Subjects: Amino Acid Motifs; Animals; Binding Sites; Cell Differentiation - physiology; Cell Line; Deoxyribonucleic acid; DNA; EMBO09; EMBO11; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; endoderm; Endoderm - cytology; Endoderm - embryology; enhancer code; Enhancer Elements, Genetic - physiology; Gene expression; Gene Expression Regulation, Developmental - physiology; Genomics; HMGB Proteins - genetics; HMGB Proteins - metabolism; Life Sciences; lineage specification; Mice; Molecular biology; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; pluripotency; Proteins; Sox/Oct interaction; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism; Transcription, Genetic - physiology; lineage specification; Sox/Oct interaction; endoderm; pluripotency; enhancer code
• DOI: 10.1038/emboj.2013.31
• ISSN: 0261-4189; 1460-2075

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. Precise, cell type‐specific signal integration is crucial for developmental fate determination. The current paper elucidates enhancer‐dependent Oct4 switching between Sox2 and Sox17 to govern self‐renewal versus endodermal differentiation.