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PMID:23495099

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Citation

Campbell, PA and Rudnicki, MA (2013) Oct4 interaction with Hmgb2 regulates Akt signaling and pluripotency. Stem Cells 31:1107-20

Abstract

In pluripotent stem cells, bivalent domains mark the promoters of developmentally regulated loci. Histones in these chromatin regions contain coincident epigenetic modifications of gene activation and repression. How these marks are transmitted to maintain the pluripotent state in daughter progeny remains poorly understood. Our study demonstrates that Oct4 post-translational modifications (PTMs) form a positive feedback loop, which promotes Akt activation and interaction with Hmgb2 and the SET complex. This preserves H3K27me3 modifications in daughter progeny and maintains the pluripotent gene expression signature in murine embryonic stem cells. However, if Oct4 is not phosphorylated, a negative feedback loop is formed that inactivates Akt and initiates the DNA damage response. Oct4 sumoylation then is required for G1/S progression and transmission of the repressive H3K27me3 mark. Therefore, PTMs regulate the ability of Oct4 to direct the spatio-temporal formation of activating and repressing complexes to orchestrate chromatin plasticity and pluripotency. Our work highlights a previously unappreciated role for Oct4 PTM-dependent interactions in maintaining restrained Akt signaling and promoting a primitive epigenetic state.

Links

PubMed Online version:10.1002/stem.1365

Keywords

Animals; Cells, Cultured; Chromatin/genetics; Chromatin/metabolism; DNA Damage/genetics; Embryonic Stem Cells/cytology; Embryonic Stem Cells/metabolism; Embryonic Stem Cells/physiology; Epigenesis, Genetic/genetics; G1 Phase/genetics; HMGB2 Protein/genetics; HMGB2 Protein/metabolism; Histones/genetics; Histones/metabolism; Mice; Octamer Transcription Factor-3/genetics; Octamer Transcription Factor-3/metabolism; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation; Pluripotent Stem Cells/cytology; Pluripotent Stem Cells/metabolism; Pluripotent Stem Cells/physiology; Polycomb-Group Proteins/genetics; Polycomb-Group Proteins/metabolism; Protein Processing, Post-Translational/genetics; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism; S Phase/genetics; Signal Transduction/genetics; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic/genetics

Significance

Annotations

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

MOUSE:PO5F1

enables

GO:0000987: cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PO5F1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HMGB2

enables

GO:0000987: cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:HMGB2

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HMGB2

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HMGB2

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HMGB2

enables

GO:0008134: transcription factor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:AKT1

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:Q3U566

enables

GO:0000987: cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:Q3U566

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:Q3U566

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:Q3U566

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:Q3U566

enables

GO:0008134: transcription factor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PO5F1

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PO5F1

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PO5F1

part_of

GO:0000790: nuclear chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PO5F1

enables

GO:0001158: enhancer sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PO5F1

enables

GO:0019955: cytokine binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PO5F1

acts_upstream_of_or_within

GO:0051898: negative regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AKT1

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_output:(PR:000037051)
  • has_input:(PR:000049954)

Seeded From UniProt

complete

Notes

See also

References

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