一種以前被認(rèn)為與X-性染色體連鎖智力發(fā)育遲緩有關(guān)的蛋白,，現(xiàn)在被發(fā)現(xiàn)通過改變組蛋白影響基因表達(dá),。含有JmjC域的蛋白SMCX（或JARID1C）是一種組蛋白去甲基化酶，它在試管中和在細(xì)胞中都能將"在賴氨酸-4處三甲基化的組蛋白H3"（H3K4me3）去甲基化,，并且能夠抑制某些神經(jīng)基因的轉(zhuǎn)錄,。該發(fā)現(xiàn)表明，SMCX的突變也許會(huì)通過染色質(zhì)上的這一效應(yīng)損害神經(jīng)基因的調(diào)控,，從而有助于發(fā)病,。
原始出處:
Nature 447, 601-605 (31 May 2007) | doi:10.1038/nature05823; Received 5 December 2006; Accepted 10 April 2007; Published online 29 April 2007
The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation
Mamta Tahiliani1,2,4, Pinchao Mei1,4, Rui Fang1, Thiago Leonor1, Michael Rutenberg1,3, Fumiko Shimizu1, Jing Li1, Anjana Rao2 & Yujiang Shi1
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and BCMP, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue
Harvard Medical School and the CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA
These authors contributed equally to this work.
Correspondence to: Yujiang Shi1 Correspondence and requests for materials should be addressed to Y.S. (Email: [email protected]).
Gene transcription is critically influenced by chromatin structure and the modification status of histone tails1. Methylation of lysine residues in histone tails is dynamically regulated by the opposing activities of histone methyltransferases and histone demethylases2. Here we show that JARID1C/SMCX, a JmjC-domain-containing protein implicated in X-linked mental retardation and epilepsy3, 4, 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 REST5, 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.
