RE1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a protein which in humans is encoded by the RESTgene, and acts as a transcriptional repressor. REST is expressly involved in the repression of neural genes in non-neuronal cells. Many genetic disorders have been tied to alterations in the REST expression pattern, including colon and small-cell lung carcinomas found with truncated versions of REST. In addition to these cancers, defects in REST have also been attributed a role in Huntington Disease, neuroblastomas, and the effects of epileptic seizures and ischaemia.
This gene encodes a transcriptional repressor which represses neuronal genes in non-neuronal tissues. It is a member of the Kruppel-type zinc fingertranscription factor family. It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element (NRSE, also known as RE1). The protein is also found in undifferentiated neuronal progenitor cells, and it is thought that this repressor may act as a master negative regulator of neurogenesis. Alternatively spliced transcript variants have been described; however, their full length nature has not been determined. REST is found to be down-regulated in elderly people with Alzheimer's disease.
REST contains 8 Cys2His2 zinc fingers and mediates gene repression by recruiting several chromatin-modifying enzymes.
NRSF bound to DNA and cofactors on each of its two cofactor binding domains.
Chromatin remodeling occurs, causing the gene to be 'turned off'.
Interesting to note that REST strongly correlate with increased longevity. REST levels are highest in the brains of people who lived up to be 90 - 100s and remained cognitively intact. Levels stayed high specifically in the brain regions vulnerable to Alzheimer's, suggesting that they might be protected from dementia. It is assumed that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity.
^Schoenherr CJ, Anderson DJ (March 1995). "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes". Science267 (5202): 1360–3. doi:10.1126/science.7871435. PMID7871435.
^ abChong JA, Tapia-Ramírez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA, Kraner SD, Mandel G (March 1995). "REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons". Cell80 (6): 949–57. doi:10.1016/0092-8674(95)90298-8. PMID7697725.
^Coulson J.M. (September 2005). "Transcriptional Regulation: Cancer, Neurons and the REST". Current Biology15 (17): R665–R668. doi:10.1016/j.cub.2005.08.032.
Ooi L and Wood IC (2007). "Chromatin crosstalk in development and disease: lessons from REST". Nat. Rev. Genet.8 (6(7)): 544–54. doi:10.1038/nrg2100. PMID17572692.
Chong JA, Tapia-Ramírez J, Kim S et al. (1995). "REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.". Cell80 (6): 949–57. doi:10.1016/0092-8674(95)90298-8. PMID7697725.CS1 maint: Explicit use of et al. (link)
Schoenherr CJ, Anderson DJ (1995). "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.". Science267 (5202): 1360–3. doi:10.1126/science.7871435. PMID7871435.
Scholl T, Stevens MB, Mahanta S, Strominger JL (1996). "A zinc finger protein that represses transcription of the human MHC class II gene, DPA.". J. Immunol.156 (4): 1448–57. PMID8568247.
Coulson J.M. (September 2005). "Transcriptional Regulation: Cancer, Neurons and the REST". Current Biology15 (17): R665–R668. doi:10.1016/j.cub.2005.08.032.
Thiel G, Lietz M, Cramer M (1998). "Biological activity and modular structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes.". J. Biol. Chem.273 (41): 26891–9. doi:10.1074/jbc.273.41.26891. PMID9756936.
Palm K, Metsis M, Timmusk T (1999). "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat.". Brain Res. Mol. Brain Res.72 (1): 30–9. doi:10.1016/S0169-328X(99)00196-5. PMID10521596.
Grimes JA, Nielsen SJ, Battaglioli E et al. (2000). "The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex.". J. Biol. Chem.275 (13): 9461–7. doi:10.1074/jbc.275.13.9461. PMID10734093.CS1 maint: Explicit use of et al. (link)
Coulson JM, Edgson JL, Woll PJ, Quinn JP (2000). "A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker.". Cancer Res.60 (7): 1840–4. PMID10766169.
Kojima T, Murai K, Naruse Y et al. (2001). "Cell-type non-selective transcription of mouse and human genes encoding neural-restrictive silencer factor.". Brain Res. Mol. Brain Res.90 (2): 174–86. doi:10.1016/S0169-328X(01)00107-3. PMID11406295.CS1 maint: Explicit use of et al. (link)
Battaglioli E, Andrés ME, Rose DW et al. (2002). "REST repression of neuronal genes requires components of the hSWI.SNF complex.". J. Biol. Chem.277 (43): 41038–45. doi:10.1074/jbc.M205691200. PMID12192000.CS1 maint: Explicit use of et al. (link)
Lunyak VV, Burgess R, Prefontaine GG et al. (2002). "Corepressor-dependent silencing of chromosomal regions encoding neuronal genes.". Science298 (5599): 1747–52. doi:10.1126/science.1076469. PMID12399542.CS1 maint: Explicit use of et al. (link)
Lietz M, Hohl M, Thiel G (2003). "RE-1 silencing transcription factor (REST) regulates human synaptophysin gene transcription through an intronic sequence-specific DNA-binding site.". Eur. J. Biochem.270 (1): 2–9. doi:10.1046/j.1432-1033.2003.03360.x. PMID12492469.
Hersh LB, Shimojo M (2003). "Regulation of cholinergic gene expression by the neuron restrictive silencer factor/repressor element-1 silencing transcription factor.". Life Sci.72 (18–19): 2021–8. doi:10.1016/S0024-3205(03)00065-1. PMID12628452.
Kemp DM, Lin JC, Habener JF (2003). "Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor". J. Biol. Chem.278 (37): 35057–62. doi:10.1074/jbc.M305891200. PMID12829700.
Zuccato C, Tartari M, Crotti A et al. (2003). "Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes". Nat. Genet.35 (1): 76–83. doi:10.1038/ng1219. PMID12881722.CS1 maint: Explicit use of et al. (link)
Martin D, Tawadros T, Meylan L et al. (2004). "Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines". J. Biol. Chem.278 (52): 53082–9. doi:10.1074/jbc.M306861200. PMID14565956.CS1 maint: Explicit use of et al. (link)