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PMID:19736317

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Citation

Stefanovic, S, Abboud, N, Désilets, S, Nury, D, Cowan, C and Pucéat, M (2009) Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate. J. Cell Biol. 186:665-73

Abstract

Oct4 exerts a dose-dependent dual action, as both a gatekeeper for stem cell pluripotency and in driving cells toward specific lineages. Here, we identify the molecular mechanism underlying this dual function. BMP2- or transgene-induced Oct4 up-regulation drives human embryonic and induced pluripotent stem cells to become cardiac progenitors. When embryonic stem cell pluripotency is achieved, Oct4 switches from the Sox2 to the Sox17 promoter. This switch allows the cells to turn off the pluripotency Oct4-Sox2 loop and to turn on the Sox17 promoter. This powerful process generates a subset of endoderm-expressing Sox17 and Hex, both regulators of paracrine signals for cardiogenesis (i.e., Wnt, BMP2) released into the medium surrounding colonies of embryonic stem cells. Our data thus reveal a novel molecular Oct4- and Sox17-mediated mechanism that disrupts the stem cell microenvironment favoring pluripotency to provide a novel paracrine endodermal environment in which cell lineage is determined and commits the cells to a cardiogenic fate.

Links

PubMed PMC2742180 Online version:10.1083/jcb.200901040

Keywords

Cell Differentiation/physiology; Cell Line; Cell Lineage; Gene Expression Regulation, Developmental; Heart/embryology; Humans; Octamer Transcription Factor-3/genetics; Octamer Transcription Factor-3/metabolism; Paracrine Communication; Pluripotent Stem Cells/cytology; Pluripotent Stem Cells/physiology; Promoter Regions, Genetic; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; SOXB1 Transcription Factors/genetics; SOXB1 Transcription Factors/metabolism; SOXF Transcription Factors/genetics; SOXF Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BMP2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0003130: BMP signaling pathway involved in heart induction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0035051: cardiocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01860

F

Seeded From UniProt

complete

HUMAN:SOX2

part_of

GO:0005667: transcription regulator complex

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PO5F1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P48431

F

Seeded From UniProt

complete

HUMAN:PO5F1

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PO5F1

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0090308: regulation of DNA methylation-dependent heterochromatin assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX17

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01860-1

F

Seeded From UniProt

complete

HUMAN:SOX17

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SOX17

involved_in

GO:0060914: heart formation

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX17

involved_in

GO:0060913: cardiac cell fate determination

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT3A

involved_in

GO:0003136: negative regulation of heart induction by canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0090308: regulation of methylation-dependent chromatin silencing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0090081: regulation of heart induction by regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0060913: cardiac cell fate determination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0060795: cell fate commitment involved in formation of primary germ layer

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0060391: positive regulation of SMAD protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0035019: somatic stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H6I2

F

Seeded From UniProt

complete

HUMAN:PO5F1

part_of

GO:0005667: transcription factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0003130: BMP signaling pathway involved in heart induction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX2

part_of

GO:0005667: transcription factor complex

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SOX2

involved_in

GO:0035019: somatic stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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