1. Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and BCMP, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue
2. Harvard Medical School and the CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
3. Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA
4. These authors contributed equally to this work.

Correspondence to: Yujiang Shi¹ Correspondence and requests for materials should be addressed to Y.S. (Email: yujiang_shi@hms.harvard.edu).

Abstract

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 epilepsy^{3, 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.

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