The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation

Abstract

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.

Epigenetic Mechanisms in Stroke and Epilepsy

“…KDM5C effects epigenetic remodeling and gene silencing by assembling with the transcriptional repressor REST and its corepressors (CoREST, HDAC1 and -2, and G9a). Notably, KDM5C promotes REST-dependent repression of a subset of target genes such as BDNF and sodium channel type 2A (SCN2A) (Tahiliani et al, 2007). These genes are of interest because increases in their activity are implicated in the pathophysiology of epilepsy (Binder et al, 2001;Shi et al, 2011).…”

“…Rather than changing chromatin structure directly, the main function of methylation is to attract proteins that can modify chromatin (Cloos, 2011). Methylation itself is also important in cognitive functions and intellectual disabilities (Tahiliani et al, 2007). Moreover, histone demethylases are implicated in diseases such as cancer, autism, X-linked mental retardation, and schizophrenia (Cloos, 2011).…”

“…KDM5C removes di-and tri-methyl marks from lysine 4 of H3 and represses gene transcription. Mutations in the histone demethylase KDM5C are linked to X-linked mental retardation and epilepsy (Tahiliani et al, 2007). KDM5C effects epigenetic remodeling and gene silencing by assembling with the transcriptional repressor REST and its corepressors (CoREST, HDAC1 and -2, and G9a).…”

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

“…Therefore, it is not surprising that several neurological disorders involve mutations in genes that encode chromatinbinding and/or -modifying enzymes. Examples include mutations in the gene encoding the chromatin-remodeling factor, ATRX, that causes a-thalassemia and X-linked mental retardation syndrome, as well as in genes encoding the histone H3K4me3-demethylase, JARID1C, that causes epilepsy X-linked mental retardation, the histone H3K9me1/2-methyltransferase complex, G9a/GLP (EHMT2/1), that results in a human mental retardation syndrome, and the histone acetyltransferase, CREB-binding protein, that causes Rubinstein-Taybi syndrome (Gibbons et al, 1995;Alarcon et al, 2004;Kleefstra et al, 2006;Tahiliani et al, 2007;Schaefer et al, 2009). A common theme of these disorders is that mutations in epigenetic regulators can alter chromatin structure and induce a broad spectrum of neurological and behavioral deficits.…”

Backbone and sidechain 1H, 13C and 15N resonance assignments of the Bright/ARID domain from the human JARID1C (SMCX) protein

“…JARID1C acts as a histone H3 lysine 4 demethylase involved in transcriptional repression (Iwase et al 2007). Mutations in JARID1C are a known cause of X-linked mental retardation (XLMR) and epilepsy, suggesting that JARID1C plays a role in human brain function (Tahiliani et al 2007;Tzschach et al 2006, Jensen et al 2005.…”