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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Survival
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DNA, Complementary
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Library
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Histone Demethylases
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / chemistry
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Histones / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Jumonji Domain-Containing Histone Demethylases
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Lysine / metabolism
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Mental Retardation, X-Linked / genetics*
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Methylation
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Mice
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Minor Histocompatibility Antigens
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neurons / cytology
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Neurons / metabolism
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Oxidoreductases, N-Demethylating / genetics*
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Oxidoreductases, N-Demethylating / metabolism
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Proteins / genetics*
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Proteins / metabolism
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Retinoblastoma-Binding Protein 2
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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DNA, Complementary
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DNA-Binding Proteins
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Histones
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Intracellular Signaling Peptides and Proteins
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Minor Histocompatibility Antigens
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Neoplasm Proteins
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Proteins
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Tumor Suppressor Proteins
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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KDM5A protein, human
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KDM5C protein, human
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KDM5D protein, human
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Kdm5b protein, mouse
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Retinoblastoma-Binding Protein 2
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Oxidoreductases, N-Demethylating
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Histone-Lysine N-Methyltransferase
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Lysine