A cohesin–OCT4 complex mediates Sox enhancers to prime an early embryonic lineage

• Published in: Nature communications Vol. 6; no. 1; p. 6749
• Main Authors: Abboud, Nesrine, Morris, Thomas Moore, Hiriart, Emilye, Yang, Henry, Bezerra, Hudson, Gualazzi, Maria-Giovanna, Stefanovic, Sonia, Guénantin, Anne-Claire, Evans, Sylvia M., Pucéat, Michel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.04.2015; Nature Publishing Group
• Subjects: 13/100; 38/15; 631/136/2086/1986; 631/337/100/102; 631/80/86; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; CCCTC-Binding Factor; Cell Cycle Proteins - metabolism; Cell fate; Chromatin Immunoprecipitation; Chromatin remodeling; Chromosomal Proteins, Non-Histone - metabolism; Cohesin; Cohesins; Cohesion; DNA-Binding Proteins - metabolism; Embryo, Mammalian - metabolism; Embryogenesis; Embryonic growth stage; Embryonic Stem Cells - metabolism; Embryos; Enhancers; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Green Fluorescent Proteins; Heart - embryology; HMGB Proteins - genetics; HMGB Proteins - metabolism; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; Kinases; Loci; Mesendoderm; Mice; multidisciplinary; Neoplasm Proteins; Oct-4 protein; Octamer Transcription Factor-3 - metabolism; Pluripotent Stem Cells; Polycomb group proteins; Polycomb Repressive Complex 1 - metabolism; Polycomb Repressive Complex 2 - metabolism; Polycomb-Group Proteins - metabolism; Real-Time Polymerase Chain Reaction; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); SOX Transcription Factors - metabolism; SOXB1 Transcription Factors - metabolism; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism; SoxS protein; Switches; Transcription; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7749

Short- and long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular events underlying these structures and how they affect cell fate decision during embryonic development are poorly understood. One of the first embryonic cell fate decisions (that is, mesendoderm determination) is driven by the POU factor OCT4, acting in concert with the high-mobility group genes Sox-2 and Sox-17 . Here we report a chromatin-remodelling mechanism and enhancer function that mediate cell fate switching. OCT4 alters the higher-order chromatin structure at both Sox-2 and Sox-17 loci. OCT4 titrates out cohesin and switches the Sox-17 enhancer from a locked (within an inter-chromosomal Sox-2 enhancer/CCCTC-binding factor CTCF/cohesin loop) to an active (within an intra-chromosomal Sox-17 promoter/enhancer/cohesin loop) state. SALL4 concomitantly mobilizes the polycomb complexes at the Sox s loci. Thus, OCT4/SALL4-driven cohesin- and polycombs-mediated changes in higher-order chromatin structure mediate instruction of early cell fate in embryonic cells. Higher order chromatin structures affect gene transcription, but how they determine cell fate is unclear. Here, the authors show that OCT4 and SALL4 alter the higher-order chromatin structure and mediate cell fate switching in embryonic cells by targeting cohesin and polycomb complexes, respectively.