The X-Linked Mental Retardation Gene SMCX/JARID1C Defines a Family of Histone H3 Lysine 4 Demethylases

Shigeki Iwase, Fei Lan, Peter Bayliss, Luis de la Torre-Ubieta, Maite Huarte, Hank H. Qi, Johnathan R R. Whetstine, Azad Bonni, Thomas M. Roberts, Yang Shi

Research output: Contribution to journalArticle

468 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1077-1088
Number of pages12
JournalCell
Volume128
Issue number6
DOIs
StatePublished - Mar 23 2007

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    Iwase, S., Lan, F., Bayliss, P., de la Torre-Ubieta, L., Huarte, M., Qi, H. H., Whetstine, JR. R., Bonni, A., Roberts, T. M., & Shi, Y. (2007). The X-Linked Mental Retardation Gene SMCX/JARID1C Defines a Family of Histone H3 Lysine 4 Demethylases. Cell, 128(6), 1077-1088. https://doi.org/10.1016/j.cell.2007.02.017