JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor.
Covalent modification of histones plays an important role in regulating chromatin dynamics and transcription. Histone methylation was thought to be an irreversible modification until recently. Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. Similar to JHDM1, JHDM2A-mediated histone demethylation requires cofactors Fe(II) and alpha-ketoglutarate. Mutational studies indicate that a JmjC domain and a zinc finger present in JHDM2A are required for its enzymatic activity. Overexpression of JHDM2A greatly reduced the H3K9 methylation level in vivo. Knockdown of JHDM2A results in an increase in the dimethyl-K9 levels at the promoter region of a subset of genes concomitant with decrease in their expression. Finally, JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.
Yamane
Kenichi
K
Howard Hughes Medical Institute, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Toumazou
Charalambos
C
Tsukada
Yu-ichi
Y
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Wong
Jiemin
J
Zhang
Yi
Y
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D020134:Catalytic Domain / Q000235:genetics; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases; D007656:Ketoglutaric Acids / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
D012739:Gonadal Steroid Hormones; D006657:Histones; D007656:Ketoglutaric Acids; D011944:Receptors, Androgen; D015534:Trans-Activators; D007501:Iron; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse; D010089:Oxidoreductases, N-Demethylating