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The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases.

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.

Pubmed ID: 17320160

Authors

  • Iwase S
  • Lan F
  • Bayliss P
  • de la Torre-Ubieta L
  • Huarte M
  • Qi HH
  • Whetstine JR
  • Bonni A
  • Roberts TM
  • Shi Y

Journal

Cell

Publication Data

March 23, 2007

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM 071004
  • Agency: NIGMS NIH HHS, Id: GM 58012
  • Agency: NIGMS NIH HHS, Id: GM 70095
  • Agency: PHS HHS, Id: NCI118487
  • Agency: NINDS NIH HHS, Id: NS051255
  • Agency: NINDS NIH HHS, Id: NS41021

Mesh Terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • DNA, Complementary
  • DNA-Binding Proteins
  • Gene Library
  • Histone Demethylases
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Lysine
  • Mental Retardation, X-Linked
  • Methylation
  • Mice
  • Neoplasm Proteins
  • Neurons
  • Oxidoreductases, N-Demethylating
  • Proteins
  • Retinoblastoma-Binding Protein 2
  • Tumor Suppressor Proteins