The REST gene spans 24 kb of genomic DNA. It is composed of: three alternative 5 non-coding exons associated with different gene promoters, three coding exons, an internal alternative exon that is spliced into some neural and disease associated transcripts.

According to Entrezgene the REST gene encodes a single reference sequence mRNA of 3663 bp (NM_005612.3) that is composed of four exons. However, the literature indicates that at least six different splice variants of REST exist and are associated with neural gene expression and certain disease states.

Isoform 1: 1097 amino acids, 122 kDa protein,
Isoform 2: (Δ314-1097), 313 amino acids, 35 kDa protein,
Isoform 3: (Δ330-1097), 329 amino acids, 37 kDa protein,
Isoform 4: (Δ304-326), 1074 amino acids, 119 kDa protein.

REST shows specific expression patterns during development, and exhibits tissue-specific, cell cycle associated or disease dependent expression. This context-dependent expression of REST is regulated through differential transcription, splicing and proteasome-mediated degradation. REST is under expressed in differentiated neuronal tissue, however it plays an essential role during embryogenesis as mice that lack REST die by embryonic day 11.5. Although these mice appear normal until embryonic day 9.5, widespread apoptotic death then results in malformations in the developing nervous system and restricted growth (Chen et al., 1998). In other adult tissues, REST is ubiquitously expressed showing preferential accumulation in tissues of the lymphocytic compartment, including spleen, thymus, peripheral blood lymphocytes, and also in ovary (Scholl et al., 1996).

REST is predicted to localize to the nucleus, however the literature reports differential localization of some isoforms. REST undergoes nucleocytoplasmic shuttling, its nuclear targeting is dependent on either a classical NLS or zinc finger 5 (Shimojo et al., 2001) and is influenced by association with other proteins such as PRICKLE1 (RILP) (Shimojo and Hersh, 2003), HTT (Zuccato et al., 2003) and DCTN1 (p150-Glued) (Shimojo, 2008). REST may also be recruited to nuclear PML bodies by association with TRF2 (Zhang et al., 2008).

REST is a transcriptional repressor with a role in regulating gene expression. It was identified in 1995 as a protein that bound to the repressor element 1 (RE1 or NRSE) motif, primarily located in promoter regions of neuron-specific genes. For this reason, REST was initially proposed to silence the transcription of neuronal genes in non-neuronal cells. However, it has subsequently emerged as both a master regulator of neurogenesis and a factor with other essential roles in both neuronal and non-neuronal cells. Indeed, inappropriate REST expression can trigger apoptosis (Lawinger et al., 2000; Neumann et al., 2004).
A combination of bioinformatics and biochemical approaches has been used to identify binding sites and potential target genes of REST. Genome-wide chromatin immunoprecipitation studies have shown that REST can occupy several thousand RE1 motifs with the potential to regulate hundreds of different genes (Johnson et al., 2007; Otto et al., 2007). REST is therefore implicated in multiple biological processes and signalling pathways, for example regulating ion channels, growth factors or hormones, cytoskeletal proteins and other transcription factors (Bruce et al., 2004). Specific examples include regulation of MAD2 that impacts on mitosis and DNA recombination (Guardavaccaro et al., 2008), many neurosecretory proteins that affect presynaptic vesicle processing and exocytosis of secreted factors (Bruce et al., 2006; Pance et al., 2006; DAlessandro et al., 2009), the deubiquitinating enzyme UCHL1 affecting ubiquitination and proteasome-mediated stability (Barrachina et al., 2007), and the VEGF receptor NRP1 that influences cell migration and angiogenesis (Kurschat et al., 2006). REST ablation impairs the production of laminin extracellular matrix components (Sun et al., 2008) and plays a role as a switch regulating potassium channel expression (Cheong et al., 2005). REST also interacts with several intracellular signal transduction cascades, including the PI3K (Westbrook et al., 2005), WNT (Nishihara et al., 2003) and Hedgehog (Gates et al., 2010) pathways. In addition to directly regulating mRNA transcription, REST also controls expression of a family of micro-RNAs that indirectly control other mRNA targets (Conaco et al., 2006), for example REST-mediated repression of micro-RNAs directs a switch of chromatin regulatory complexes essential for the transition to post-mitotic neurons (Yoo et al., 2009).
REST mediates its actions through interaction with a large repertoire of proteins that modify chromatin including the transcriptional repressor SIN3A/SIN3B at RD1, and the methylated CpG binding protein MeCP2 (Lunyak et al., 2002) along with many others at RD2. For example, the SMARCA4 (BRG1), SMARCC2 (BAF170) and SMARCE1 (BAF57) components of the SWI/SNF ATP-dependent chromatin-remodeling complex are recruited (Battaglioli et al., 2002). RCOR1 (coREST) is also recruited by REST to occupy RE1, and co-ordinates assembly of the BHC complex comprising the SWI/SNF component HMG20 (BRAF35), the scaffold PHF21A (BHC80), the histone deacetylases HDAC1/HDAC2 and the H3K4 demethylase KDM1A (LSD1) (Lee et al., 2005). Recruitment of the H3K9/H3K27 methyltransferase EHMT2 (G9a) (Roopra et al., 2004) appears to be dependent on MED12 (Ding et al., 2008) and CDYL (Mulligan et al., 2008). Together these complexes mediate transcriptional repression by remodeling chromatin so that histones become more tightly associated with DNA and less accessible to the transcriptional machinery (Ooi and Wood, 2007).

REST is a member of the mammalian family of Krüppel-type zinc finger transcription factors. The closest paralog based on sequence homology to REST is ZNF407.

Deletions of varying size encompassing the REST locus on chromosome 4 were detected in one-third of primary human colon tumors and colon cancer cell lines, suggesting that chromosomal deletions targeting REST are a frequent event in colon cancer (Westbrook et al., 2005). The REST locus has also been implicated in brain tumors, as an amplification site identified in human malignant glioma mapped to chromosome 4q12 (Schrock et al., 1994) and this region was lost in 30-80% of oligodendrogliomas or anaplastic oligodendrogliomas (Zhu et al., 1998). Another study of 161 patients diagnosed with nervous system tumors also screened samples for genetic alterations in REST (Blom et al., 2006). Although two non-synonymous SNPs were found in REST exon 3, which might affect the capacity of REST to bind target DNA, these were germ line changes and no cancer-associated truncating or activating mutations of REST were found. The same study reported low-level amplification of REST in both glioma and medulloblastoma, although high-level amplification was rare.