TY - JOUR
T1 - The X-Linked Mental Retardation Gene SMCX/JARID1C Defines a Family of Histone H3 Lysine 4 Demethylases
AU - Iwase, Shigeki
AU - Lan, Fei
AU - Bayliss, Peter
AU - de la Torre-Ubieta, Luis
AU - Huarte, Maite
AU - Qi, Hank H.
AU - Whetstine, Johnathan R R.
AU - Bonni, Azad
AU - Roberts, Thomas M.
AU - Shi, Yang
N1 - Funding Information:
We thank Gongyi Zhang, Lars Riff Jensen, and Andreas Kuß for helpful discussion. J.R.W. and L.T.U. are recipients of the Ruth L. Kirschstein National Service Award (GM 70095) and National Science Foundation Fellowship, respectively. This work was supported by grants from the National Institutes of Health (NS051255 and NS41021 to A.B.; and GM 58012, GM 071004, and NCI118487 to Y.S.), a postdoctoral fellowship from Canadian Institute of Health Research (CIHR to H.H.Q.), and in part by a grant from the Novartis Biomedical Research Institute to Y.S.
PY - 2007/3/23
Y1 - 2007/3/23
N2 - Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4me3 demethylases and uncover a critical link between histone modifications and XLMR.
AB - Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4me3 demethylases and uncover a critical link between histone modifications and XLMR.
UR - http://www.scopus.com/inward/record.url?scp=33947302685&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2007.02.017
DO - 10.1016/j.cell.2007.02.017
M3 - Article
C2 - 17320160
AN - SCOPUS:33947302685
SN - 0092-8674
VL - 128
SP - 1077
EP - 1088
JO - Cell
JF - Cell
IS - 6
ER -