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Gene Section Review

REST (RE1 -silencing ) Monica Faronato, Judy M Coulson Physiology Department, School of Biomedical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK (MF, JMC)

Published in Atlas Database: May 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/RESTID44266ch4q12.html DOI: 10.4267/2042/44968 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

It is composed of: three alternative 5' non-coding exons Identity associated with different promoters, three coding Other names: NRSF, XBR exons, an internal alternative exon that is spliced into HGNC (Hugo): REST some neural and disease associated transcripts. Location: 4q12 Transcription Note: REST/NRSF negatively regulates the According to Entrezgene the REST gene encodes a transcription of containing RE1 sites (Chong et single reference sequence mRNA of 3663 bp al., 1995; Schoenherr and Anderson, 1995). REST has (NM_005612.3) that is composed of four exons. context dependent roles as both a tumour suppressor However, the literature indicates that at least six and an oncogene (Coulson, 2005). different splice variants of REST exist and are associated with neural and certain DNA/RNA disease states.

Description The REST gene spans 24 kb of genomic DNA.

Schematic illustrating REST mRNA and alternative splice variants. The human REST gene is shown (top) illustrating the three main exons (dark blue), an alternative exon (light blue) and one of three alternative 5' non-coding exons (white). The approximate position of sequence encoding eight zinc fingers are illustrated by boxes, these are associated with DNA binding (white) or nuclear import (red). Six alternative mRNAs are illustrated below, the REST reference sequence (NM_005612.3) codes for the major isoform 1. Splice variants described in human *neuroblastoma (Palm et al., 1999) or **SCLC (Coulson et al., 2000) are also shown. REST 1 and REST-5F ∆ code for isoform 2 or isoform 4 respectively. The alternative exon in REST-N62, REST-N4 and sNRSF (N50) introduces a premature stop codon and all three transcripts encode isoform 3 (sNRSF/REST4).

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Schematic illustrating REST and alternative isoforms. Uniprot.org shows the existence of 4 REST isoforms. Isoform 1 is the canonical sequence; it comprises two repression domains (RD1 and RD2), lysine-rich (400-603) and proline-rich (595-815) domains, a DNA binding domain (159-412) of eight zinc fingers (boxes), two nuclear localization signals (shown in red), a phosphodegron (E1009/S1013 or S1027/S1030) and a ninth C-terminal (1006-1082). REST can recruit a variety of transcriptional co- repressors through interaction at RD1 or RD2; examples are illustrated including Sin3A (interaction maps to 32-122), Sin3B (43-57) and RCOR1 (1009-1087). Isoform 2 is truncated, retaining only zinc fingers 1-4 and localizes to the cytoplasm. Isoform 3, also called REST4 or sNRSF, is expressed in neuroblastoma and SCLC; it lacks RD2 and has a truncated DNA binding domain, but retains zinc fingers 1-5 and nuclear localization. Isoform 4 has selective deletion of zinc finger 5. (Palm et al., 1999; Coulson et al., 2000; Shimojo et al., 2001).

tissues, REST is ubiquitously expressed showing Protein preferential accumulation in tissues of the lymphocytic Description compartment, including spleen, thymus, peripheral blood lymphocytes, and also in ovary (Scholl et al., Isoform 1: 1097 amino acids, 122 kDa protein, 1996). Isoform 2: ( ∆314-1097), 313 amino acids, 35 kDa protein, Localisation Isoform 3: ( ∆330-1097), 329 amino acids, 37 kDa REST is predicted to localize to the nucleus, however protein, the literature reports differential localization of some Isoform 4: ( ∆304-326), 1074 amino acids, 119 kDa isoforms. REST undergoes nucleocytoplasmic protein. shuttling, its nuclear targeting is dependent on either a classical NLS or zinc finger 5 (Shimojo et al., 2001) Expression and is influenced by association with other REST shows specific expression patterns during such as PRICKLE1 (RILP) (Shimojo and Hersh, 2003), development, and exhibits tissue-specific, cell cycle HTT (Zuccato et al., 2003) and DCTN1 (p150-Glued) associated or disease dependent expression. This (Shimojo, 2008). REST may also be recruited to context-dependent expression of REST is regulated nuclear PML bodies by association with TRF2 (Zhang through differential transcription, splicing and et al., 2008). proteasome-mediated degradation. REST is under expressed in differentiated neuronal tissue, however it Function plays an essential role during embryogenesis as mice REST is a transcriptional repressor with a role in that lack REST die by embryonic day 11.5. Although regulating gene expression. It was identified in 1995 as these mice appear normal until embryonic day 9.5, a protein that bound to the repressor element 1 (RE1 or widespread apoptotic death then results in NRSE) motif, primarily located in promoter regions of malformations in the developing nervous system and neuron-specific genes. For this reason, REST was restricted growth (Chen et al., 1998). In other adult initially proposed to silence the transcription of

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) 209 REST (RE1-silencing transcription factor) Faronato M, Coulson JM

neuronal genes in non-neuronal cells. However, it has dependent on MED12 (Ding et al., 2008) and CDYL subsequently emerged as both a master regulator of (Mulligan et al., 2008). Together these complexes neurogenesis and a factor with other essential roles in mediate transcriptional repression by remodeling both neuronal and non-neuronal cells. Indeed, chromatin so that histones become more tightly inappropriate REST expression can trigger apoptosis associated with DNA and less accessible to the (Lawinger et al., 2000; Neumann et al., 2004). transcriptional machinery (Ooi and Wood, 2007). A combination of bioinformatics and biochemical Homology approaches has been used to identify binding sites and potential target genes of REST. Genome-wide REST is a member of the mammalian family of chromatin immunoprecipitation studies have shown Krüppel-type zinc finger transcription factors. The that REST can occupy several thousand RE1 motifs closest paralog based on to REST with the potential to regulate hundreds of different is ZNF407. genes (Johnson et al., 2007; Otto et al., 2007). REST is therefore implicated in multiple biological processes Mutations and signalling pathways, for example regulating ion channels, growth factors or hormones, cytoskeletal Somatic proteins and other transcription factors (Bruce et al., Deletions of varying size encompassing the REST 2004). Specific examples include regulation of MAD2 locus on 4 were detected in one-third of that impacts on mitosis and DNA recombination primary human colon tumors and colon cancer cell (Guardavaccaro et al., 2008), many neurosecretory lines, suggesting that chromosomal deletions targeting proteins that affect presynaptic vesicle processing and REST are a frequent event in colon cancer (Westbrook exocytosis of secreted factors (Bruce et al., 2006; Pance et al., 2005). The REST locus has also been implicated et al., 2006; D'Alessandro et al., 2009), the in brain tumors, as an amplification site identified in deubiquitinating enzyme UCHL1 affecting human malignant glioma mapped to chromosome 4q12 ubiquitination and proteasome-mediated stability (Schrock et al., 1994) and this region was lost in 30- (Barrachina et al., 2007), and the VEGF NRP1 80% of oligodendrogliomas or anaplastic that influences cell migration and angiogenesis oligodendrogliomas (Zhu et al., 1998). Another study (Kurschat et al., 2006). REST ablation impairs the of 161 patients diagnosed with nervous system tumors production of laminin extracellular matrix components also screened samples for genetic alterations in REST (Sun et al., 2008) and plays a role as a switch (Blom et al., 2006). Although two non-synonymous regulating potassium channel expression (Cheong et al., SNPs were found in REST exon 3, which might affect 2005). REST also interacts with several intracellular the capacity of REST to bind target DNA, these were signal transduction cascades, including the PI3K germ line changes and no cancer-associated truncating (Westbrook et al., 2005), WNT (Nishihara et al., 2003) or activating mutations of REST were found. The same and Hedgehog (Gates et al., 2010) pathways. In study reported low-level amplification of REST in both addition to directly regulating mRNA transcription, glioma and medulloblastoma, although high-level REST also controls expression of a family of micro- amplification was rare. RNAs that indirectly control other mRNA targets (Conaco et al., 2006), for example REST-mediated Implicated in repression of micro-RNAs directs a switch of chromatin regulatory complexes essential for the Colon cancer transition to post-mitotic neurons (Yoo et al., 2009). Note REST mediates its actions through interaction with a Deletions of the chromosome 4q12, region where large repertoire of proteins that modify chromatin REST is located, are frequent events in colon cancer. including the transcriptional repressor SIN3A/SIN3B at Cytogenetics RD1, and the methylated CpG binding protein MeCP2 A single nucleotide deletion within REST exon 4 was (Lunyak et al., 2002) along with many others at RD2. identified in one cell line derived from colorectal For example, the SMARCA4 (BRG1), SMARCC2 adenocarcinoma. This results in a frameshift mutation (BAF170) and SMARCE1 (BAF57) components of the and expression of REST-FS, a truncated variant with SWI/SNF ATP-dependent chromatin-remodeling eight zinc fingers, but lacking the C-terminal repression complex are recruited (Battaglioli et al., 2002). RCOR1 domain RD2 (Westbrook et al., 2005). (coREST) is also recruited by REST to occupy RE1, and co-ordinates assembly of the BHC complex Small cell lung carcinoma (SCLC) comprising the SWI/SNF component HMG20 Note (BRAF35), the scaffold PHF21A (BHC80), the histone Altered REST function is associated with SCLC, deacetylases HDAC1/HDAC2 and the H3K4 because of reduced REST expression and an increased demethylase KDM1A (LSD1) (Lee et al., 2005). production of the REST splice variant sNRSF, that Recruitment of the H3K9/H3K27 methyltransferase lacks part of the DNA-binding domain and the C- EHMT2 (G9a) (Roopra et al., 2004) appears to be

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terminal repression domain RD2 (Coulson et al., 2000). Medulloblastoma This leads to inappropriate expression of genes like Note arginine vasopressin and the glycine receptor alpha in REST expression is generally low in adult brain SCLC (Coulson et al., 1999; Neumann et al., 2004). permitting expression of RE1-restricted neuronal genes. Prognosis However, REST is elevated in medulloblastoma cell For all types and stages of lung cancer diagnosed in the lines and in 80% of human medulloblastoma tumors UK, the 1-year and 5-year survival is 28% and 8% relatively to normal cerebellum sections, suggestive of respectively (Cancer Research UK CancerStats, 2006). an oncogenic role. Blocking endogenous REST SCG3 mRNA, a component of the REST-dependent function results in neuronal gene re-expression and neurosecretory transcriptional profile in lung cancer apoptosis in both in vitro and in vivo medulloblastoma cells, was evaluated as a biomarker for noninvasive models (Lawinger et al., 2000; Fuller et al., 2005). monitoring of neuroendocrine lung cancers and found Neuroblastoma to be associated with poor prognosis in limited disease SCLC patients (Moss et al., 2009). Note Alternative splice variants of REST were identified in Non small cell lung carcinoma (NSCLC) murine and human neuroblastoma. It was suggested Note that changes in the structure or regulation of the REST BRM/BRG1 are integral components of the SWI/SNF gene may reflect or lead to the formation and chromatin-remodeling complex, which forms part of a progression of neuroblastoma tumors, and that the larger repression complex associated with REST. Loss neuronal-specific exon/flanking introns may define a of BRM/BRG1 is observed in some human NSCLC locus of somatic recombination (Palm et al., 1999). cell lines, and leads to de-repression of REST-restricted Huntington's disease genes (Watanabe et al., 2006). Note Prognosis Wild type huntingtin protein (HTT) sequesters REST in Around 10% of NSCLC patients are reported to have the cytoplasm, inhibiting its function, whereas the BRM/BRG1 deficient lung carcinoma and this is mutant HTT protein cannot interact with REST associated with poor prognosis (Reisman et al., 2003; resulting in higher levels of REST in the nucleus and Fukuoka et al., 2004). repression of many target genes (Zuccato et al., 2007). Breast cancer Ischemia Note Note A tumor suppressor function for REST was identified Global ischemia triggers REST mRNA and protein through an RNAi library screen for genes that expression. Knockdown of the REST gene rescues contributed to transformation in a breast cancer model post-ischemic neurons from ischemia-induced cell associated with PI3K signaling (Westbrook et al., death in an in vitro model (Calderone et al., 2003). 2005). The TAC1 gene has been implicated in the development of breast and other cancers through Epilepsy production of peptides including substance P, which Note mediate resistance to apoptosis and radiation therapy. It REST and the REST4 variant are differentially was recently shown that, together with NFkB, REST regulated in rodent hippocampal seizure models and represses TAC1 expression in mesenchymal stem cells. correlate with expression of the proconvulsant However, the level of REST decreases in breast cancer substance P (Spencer et al., 2006). PRICKLE1 cells and inversely correlates with substance P (REST/NRSF interacting LIM domain protein) production and an aggressive cellular phenotype normally binds to REST mediating its translocation to (Reddy et al., 2009). the cytoplasm, thereby preventing REST from silencing Prostate cancer target genes. A PRICKLE1 mutation identified in individuals with progressive myoclonus epilepsy Note blocks the PRICKLE1 and REST interaction in vitro, Prostate tumors with a prominent neuroendocrine resulting in constitutively active REST and component are typically androgen independent and inappropriate downregulation of REST target genes highly aggressive. In prostate adenocarcinoma cells, (Bassuk et al., 2008). this acquisition of a neuroendocrine phenotype is associated with tumor progression and REST/NRSF References levels decrease as the androgen resistance progresses. This directly induces IB1/JIP-1 transcription, which in Schröck E, Thiel G, Lozanova T, du Manoir S, Meffert MC, turn modulates the JNK signaling pathway (Tawadros Jauch A, Speicher MR, Nürnberg P, Vogel S, Jänisch W. et al., 2005). Comparative genomic hybridization of human malignant gliomas reveals multiple amplification sites and nonrandom

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a transcriptional repressor of neuropilin-1 and diminishes the links epigenetic silencing of neuronal gene expression with x- ability of semaphorin 3A to inhibit keratinocyte migration. J Biol linked mental retardation. Mol Cell. 2008 Aug 8;31(3):347-59 Chem. 2006 Feb 3;281(5):2721-9 Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Pance A, Livesey FJ, Jackson AP. A role for the transcriptional Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, repressor REST in maintaining the phenotype of Hernando E, Pagano M. Control of chromosome stability by neurosecretory-deficient PC12 cells. J Neurochem. 2006 the beta-TrCP-REST-Mad2 axis. Nature. 2008 Mar Dec;99(5):1435-44 20;452(7185):365-9 Spencer EM, Chandler KE, Haddley K, Howard MR, Hughes Mulligan P, Westbrook TF, Ottinger M, Pavlova N, Chang B, D, Belyaev ND, Coulson JM, Stewart JP, Buckley NJ, Kipar A, Macia E, Shi YJ, Barretina J, Liu J, Howley PM, Elledge SJ, Walker MC, Quinn JP. Regulation and role of REST and Shi Y. 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A homozygous This article should be referenced as such: mutation in human PRICKLE1 causes an autosomal-recessive Faronato M, Coulson JM. REST (RE1-silencing transcription progressive myoclonus epilepsy-ataxia syndrome. Am J Hum factor). Atlas Genet Cytogenet Oncol Haematol. 2011; Genet. 2008 Nov;83(5):572-81 15(2):208-213. Ding N, Zhou H, Esteve PO, Chin HG, Kim S, Xu X, Joseph SM, Friez MJ, Schwartz CE, Pradhan S, Boyer TG. Mediator

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