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PMID:16079795

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Citation

Metzger, E, Wissmann, M, Yin, N, Müller, JM, Schneider, R, Peters, AH, Günther, T, Buettner, R and Schüle, R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436-9

Abstract

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.

Links

PubMed Online version:10.1038/nature04020

Keywords

Androgens; Animals; Cell Line; Cell Line, Tumor; Cell Proliferation/drug effects; Chromatin/metabolism; Gene Expression Profiling; Gene Expression Regulation/drug effects; Histone Demethylases; Histones/chemistry; Histones/metabolism; Humans; Immunoprecipitation; Male; Methylation/drug effects; Mice; Oxidoreductases, N-Demethylating/antagonists & inhibitors; Oxidoreductases, N-Demethylating/genetics; Oxidoreductases, N-Demethylating/metabolism; Pargyline/pharmacology; Prostate/metabolism; Prostatic Neoplasms/genetics; Prostatic Neoplasms/metabolism; Protein Binding; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, Androgen/genetics; Receptors, Androgen/metabolism; Transcription, Genetic/drug effects; Transcriptional Activation

Significance

Annotations

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

HUMAN:KDM1A

enables

GO:0032454: histone H3-methyl-lysine-9 demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM1A

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0030374: nuclear receptor coactivator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0030374: nuclear receptor transcription coactivator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0032454: histone demethylase activity (H3-K9 specific)

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM1A

involved_in

GO:0033169: histone H3-K9 demethylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0050681: androgen receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM1A

involved_in

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM1A

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0032452: histone demethylase activity

ECO:0000269: experimental evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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