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PMID:17938240

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Citation

Loh, YH, Zhang, W, Chen, X, George, J and Ng, HH (2007) Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev. 21:2545-57

Abstract

Embryonic stem (ES) cells are pluripotent cells with the ability to self-renew indefinitely. These unique properties are controlled by genetic factors and chromatin structure. The exit from the self-renewing state is accompanied by changes in epigenetic chromatin modifications such as an induction in the silencing-associated histone H3 Lys 9 dimethylation and trimethylation (H3K9Me2/Me3) marks. Here, we show that the H3K9Me2 and H3K9Me3 demethylase genes, Jmjd1a and Jmjd2c, are positively regulated by the ES cell transcription factor Oct4. Interestingly, Jmjd1a or Jmjd2c depletion leads to ES cell differentiation, which is accompanied by a reduction in the expression of ES cell-specific genes and an induction of lineage marker genes. Jmjd1a demethylates H3K9Me2 at the promoter regions of Tcl1, Tcfcp2l1, and Zfp57 and positively regulates the expression of these pluripotency-associated genes. Jmjd2c acts as a positive regulator for Nanog, which encodes for a key transcription factor for self-renewal in ES cells. We further demonstrate that Jmjd2c is required to reverse the H3K9Me3 marks at the Nanog promoter region and consequently prevents transcriptional repressors HP1 and KAP1 from binding. Our results connect the ES cell transcription circuitry to chromatin modulation through H3K9 demethylation in pluripotent cells.

Links

PubMed PMC2000320 Online version:10.1101/gad.1588207

Keywords

Animals; Cell Differentiation; Cell Proliferation; Chromatin Immunoprecipitation; DNA-Binding Proteins/genetics; Embryonic Stem Cells/cytology; Embryonic Stem Cells/enzymology; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Histones/chemistry; Histones/metabolism; Homeodomain Proteins/genetics; Jumonji Domain-Containing Histone Demethylases; Lysine/chemistry; Mice; Models, Biological; Nanog Homeobox Protein; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Octamer Transcription Factor-3/metabolism; Oxidoreductases, N-Demethylating/genetics; Oxidoreductases, N-Demethylating/metabolism; Pluripotent Stem Cells/cytology; Pluripotent Stem Cells/enzymology; Proto-Oncogene Proteins/metabolism; RNA Interference

Significance

Annotations

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

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:TCL1A

involved_in

GO:2000036: regulation of stem cell population maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2446210

P

Seeded From UniProt

complete

MOUSE:TCL1A

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM3A

involved_in

GO:2000036: regulation of stem cell population maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1097166

P

Seeded From UniProt

complete

MOUSE:KDM3A

involved_in

GO:2000736: regulation of stem cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM3A

involved_in

GO:0010468: regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM3A

involved_in

GO:0033169: histone H3-K9 demethylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NANOG

involved_in

GO:0019827: stem cell population maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1924054

P

Seeded From UniProt

complete

MOUSE:KDM4C

involved_in

GO:2000736: regulation of stem cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM4C

involved_in

GO:0019827: stem cell population maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1919200

P

Seeded From UniProt

complete

MOUSE:KDM4C

involved_in

GO:0010468: regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM4C

involved_in

GO:0033169: histone H3-K9 demethylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PO5F1

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PO5F1

acts_upstream_of_or_within

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PO5F1

enables

GO:0001162: RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TCL1A

acts_upstream_of_or_within

GO:2000036: regulation of stem cell population maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2446210

P

Seeded From UniProt

complete

MOUSE:TCL1A

acts_upstream_of_or_within

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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