The retinoblastoma binding protein RBP2 is an H3K4 demethylase.
Changes in histone methylation status regulate chromatin structure and DNA-dependent processes such as transcription. Recent studies indicate that, analogous to other histone modifications, histone methylation is reversible. Retinoblastoma binding protein 2 (RBP2), a nuclear protein implicated in the regulation of transcription and differentiation by the retinoblastoma tumor suppressor protein, contains a JmjC domain recently defined as a histone demethylase signature motif. Here we report that RBP2 is a demethylase that specifically catalyzes demethylation on H3K4, whose methylation is normally associated with transcriptionally active genes. RBP2-/- mouse cells displayed enhanced transcription of certain cytokine genes, which, in the case of SDF1, was associated with increased H3K4 trimethylation. Furthermore, RBP2 specifically demethylated H3K4 in biochemical and cell-based assays. These studies provide mechanistic insights into transcriptional regulation by RBP2 and provide the first example of a mammalian enzyme capable of erasing trimethylated H3K4.
Klose
Robert J
RJ
Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yan
Qin
Q
Tothova
Zuzana
Z
Yamane
Kenichi
K
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Gilliland
D Gary
DG
Zhang
Yi
Y
Kaelin
William G
WG
D000818:Animals; D016207:Cytokines / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D004625:Embryo, Nonmammalian; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D012177:Retinol-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054840:Retinol-Binding Proteins, Cellular; D018411:Spodoptera / Q000166:cytology; D014158:Transcription, Genetic
D016207:Cytokines; D006657:Histones; C518460:Rbp2 protein, mouse; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular