Gene transcription is critically influenced by chromatin structure and the 
modification status of histone tails. Methylation of lysine residues in histone 
tails is dynamically regulated by the opposing activities of histone 
methyltransferases and histone demethylases. Here we show that JARID1C/SMCX, a 
JmjC-domain-containing protein implicated in X-linked mental retardation and 
epilepsy, possesses H3K4 tri-demethylase activity and functions as a 
transcriptional repressor. An SMCX complex isolated from HeLa cells contains 
additional chromatin modifiers (the histone deacetylases HDAC1 and HDAC2, and 
the histone H3K9 methyltransferase G9a) and the transcriptional repressor REST, 
suggesting a direct role for SMCX in chromatin dynamics and REST-mediated 
repression. Chromatin immunoprecipitation reveals that SMCX and REST co-occupy 
the neuron-restrictive silencing elements in the promoters of a subset of REST 
target genes. RNA-interference-mediated depletion of SMCX derepresses several of 
these targets and simultaneously increases H3K4 trimethylation at the sodium 
channel type 2A (SCN2A) and synapsin I (SYN1) promoters. We propose that loss of 
SMCX activity impairs REST-mediated neuronal gene regulation, thereby 
contributing to SMCX-associated X-linked mental retardation.