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.
Iwase
Shigeki
S
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Lan
Fei
F
Bayliss
Peter
P
de la Torre-Ubieta
Luis
L
Huarte
Maite
M
Qi
Hank H
HH
Whetstine
Johnathan R
JR
Bonni
Azad
A
Roberts
Thomas M
TM
Shi
Yang
Y
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015723:Gene Library; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine / Q000378:metabolism; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008745:Methylation; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D056485:Retinoblastoma-Binding Protein 2; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C070050:KDM5A protein, human; C086877:KDM5C protein, human; C095561:KDM5D protein, human; C485614:Kdm5b protein, mouse; D056485:Retinoblastoma-Binding Protein 2; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine