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 ischemia.
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. REST is also responsible for ischaemia induced neuronal cell death, in mouse models of brain ischaemia. Ischaemia, which results from reduced blood profusion of tisssues, decreasing nutrient and oxygen supply, induces REST transcription and nuclear accumulation, leading to the epigenetic repression of neuronal genes leading to cell death. The mechanism beyond REST induction in ischaemia, might be tightly linked to its oxygen-dependent nuclear translocation and repression of target genes in hypoxia (low oxygen) where REST fulfils the functions of a master regulator of gene repression in hypoxia.
^Schoenherr CJ, Anderson DJ (March 1995). "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes". Science. 267 (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". Cell. 80 (6): 949–57. doi:10.1016/0092-8674(95)90298-8. PMID7697725.
Ooi L & Wood IC (July 2007). "Chromatin crosstalk in development and disease: lessons from REST". Nature Reviews Genetics. 8 (7): 544–54. doi:10.1038/nrg2100. PMID17572692.
Chong 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". Cell. 80 (6): 949–57. doi:10.1016/0092-8674(95)90298-8. PMID7697725.
Schoenherr CJ, Anderson DJ (March 1995). "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes". Science. 267 (5202): 1360–3. doi:10.1126/science.7871435. PMID7871435.
Scholl T, Stevens MB, Mahanta S, Strominger JL (February 1996). "A zinc finger protein that represses transcription of the human MHC class II gene, DPA". Journal of Immunology. 156 (4): 1448–57. PMID8568247.
Thiel G, Lietz M, Cramer M (October 1998). "Biological activity and modular structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes". The Journal of Biological Chemistry. 273 (41): 26891–9. doi:10.1074/jbc.273.41.26891. PMID9756936.
Palm K, Metsis M, Timmusk T (September 1999). "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat". Brain Research. Molecular Brain Research. 72 (1): 30–9. doi:10.1016/S0169-328X(99)00196-5. PMID10521596.
Grimes JA, Nielsen SJ, Battaglioli E, Miska EA, Speh JC, Berry DL, Atouf F, Holdener BC, Mandel G, Kouzarides T (March 2000). "The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex". The Journal of Biological Chemistry. 275 (13): 9461–7. doi:10.1074/jbc.275.13.9461. PMID10734093.
Coulson JM, Edgson JL, Woll PJ, Quinn JP (April 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 Research. 60 (7): 1840–4. PMID10766169.
Kojima T, Murai K, Naruse Y, Takahashi N, Mori N (June 2001). "Cell-type non-selective transcription of mouse and human genes encoding neural-restrictive silencer factor". Brain Research. Molecular Brain Research. 90 (2): 174–86. doi:10.1016/S0169-328X(01)00107-3. PMID11406295.
Battaglioli E, Andrés ME, Rose DW, Chenoweth JG, Rosenfeld MG, Anderson ME, Mandel G (October 2002). "REST repression of neuronal genes requires components of the hSWI.SNF complex". The Journal of Biological Chemistry. 277 (43): 41038–45. doi:10.1074/jbc.M205691200. PMID12192000.
Lietz M, Hohl M, Thiel G (January 2003). "RE-1 silencing transcription factor (REST) regulates human synaptophysin gene transcription through an intronic sequence-specific DNA-binding site". European Journal of Biochemistry / FEBS. 270 (1): 2–9. doi:10.1046/j.1432-1033.2003.03360.x. PMID12492469.
Hersh LB, Shimojo M (March 2003). "Regulation of cholinergic gene expression by the neuron restrictive silencer factor/repressor element-1 silencing transcription factor". Life Sciences. 72 (18-19): 2021–8. doi:10.1016/S0024-3205(03)00065-1. PMID12628452.
Kemp DM, Lin JC, Habener JF (September 2003). "Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor". The Journal of Biological Chemistry. 278 (37): 35057–62. doi:10.1074/jbc.M305891200. PMID12829700.
Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E (September 2003). "Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes". Nature Genetics. 35 (1): 76–83. doi:10.1038/ng1219. PMID12881722.
Martin D, Tawadros T, Meylan L, Abderrahmani A, Condorelli DF, Waeber G, Haefliger JA (December 2003). "Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines". The Journal of Biological Chemistry. 278 (52): 53082–9. doi:10.1074/jbc.M306861200. PMID14565956.