The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.
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.
Tahiliani
Mamta
M
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and BCMP, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue Boston, Massachusetts 02115, USA.
Mei
Pinchao
P
Fang
Rui
R
Leonor
Thiago
T
Rutenberg
Michael
M
Shimizu
Fumiko
F
Li
Jing
J
Rao
Anjana
A
Shi
Yujiang
Y
D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation / Q000235:genetics*; D006367:HeLa Cells; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism*; D018411:Spodoptera; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
D002843:Chromatin; D056466:Histone Demethylases; D006657:Histones; D046912:Multiprotein Complexes; D010089:Oxidoreductases, N-Demethylating; D011506:Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C086877:KDM5C protein, human