Abstract
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 Soxs loci. Thus, OCT4/SALL4-driven cohesin- and polycombs-mediated changes in higher-order chromatin structure mediate instruction of early cell fate in embryonic cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CCCTC-Binding Factor
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Cell Cycle Proteins / metabolism*
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Chromatin Immunoprecipitation
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Chromosomal Proteins, Non-Histone / metabolism*
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Cohesins
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian / metabolism*
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Embryonic Stem Cells / metabolism
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Gene Expression Regulation, Developmental
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Gene Knockdown Techniques
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Green Fluorescent Proteins
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HMGB Proteins / genetics
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HMGB Proteins / metabolism
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Heart / embryology*
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Human Embryonic Stem Cells / metabolism*
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Humans
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Mice
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Neoplasm Proteins
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Octamer Transcription Factor-3 / metabolism*
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Pluripotent Stem Cells
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Polycomb Repressive Complex 1 / metabolism
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Polycomb Repressive Complex 2 / metabolism
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Polycomb-Group Proteins / metabolism
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Real-Time Polymerase Chain Reaction
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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SOX Transcription Factors / metabolism*
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SOXB1 Transcription Factors / metabolism
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SOXF Transcription Factors / genetics
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SOXF Transcription Factors / metabolism
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Transcription Factors / metabolism
Substances
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BMI1 protein, human
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Basic Helix-Loop-Helix Transcription Factors
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CCCTC-Binding Factor
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CTCF protein, human
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Cell Cycle Proteins
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Chromosomal Proteins, Non-Histone
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Ctcf protein, mouse
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DNA-Binding Proteins
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HMGB Proteins
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Mesp1 protein, mouse
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Neoplasm Proteins
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Polycomb-Group Proteins
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Pou5f1 protein, mouse
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Repressor Proteins
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SALL4 protein, human
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SOX Transcription Factors
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SOXB1 Transcription Factors
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SOXF Transcription Factors
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SUZ12 protein, human
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Sall4 protein, mouse
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Sox17 protein, mouse
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Sox2 protein, mouse
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Transcription Factors
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Green Fluorescent Proteins
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Polycomb Repressive Complex 2
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Polycomb Repressive Complex 1