RE1-silencing transcription factor explained

RE1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a protein which in humans is encoded by the REST gene, and acts as a transcriptional repressor.^{[1] [2] [3]} REST is expressly involved in the repression of neural genes in non-neuronal cells.^{[3] [4]} 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.^[5] 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.

Function

This gene encodes a transcriptional repressor which represses neuronal genes in non-neuronal tissues. It is a member of the Kruppel-type zinc finger transcription 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.^[1] REST is found to be down-regulated in elderly people with Alzheimer's disease.^[6]

REST contains 8 Cys₂His₂ zinc fingers and mediates gene repression by recruiting several chromatin-modifying enzymes.^[7]

REST is also responsible for ischaemia induced neuronal cell death, in mouse models of brain ischaemia. Ischaemia, which results from reduced blood perfusion of tissues, decreasing nutrient and oxygen supply, induces REST transcription and nuclear accumulation, leading to the epigenetic repression of neuronal genes leading to cell death.^[8] 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.^[9]

Interactions

RE1-silencing transcription factor has been shown to interact with RCOR1.^[10]

Further reading

• Ooi L, Wood IC . Chromatin crosstalk in development and disease: lessons from REST . Nature Reviews Genetics . 8 . 7 . 544–54 . July 2007 . 17572692 . 10.1038/nrg2100 . 415873 .
• Chong JA, Tapia-Ramírez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA, Kraner SD, Mandel G . REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons . Cell . 80 . 6 . 949–57 . March 1995 . 7697725 . 10.1016/0092-8674(95)90298-8 . 6412634 . free .
• Schoenherr CJ, Anderson DJ . The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes . Science . 267 . 5202 . 1360–3 . March 1995 . 7871435 . 10.1126/science.7871435 . 1995Sci...267.1360S . 25101475 .
• Scholl T, Stevens MB, Mahanta S, Strominger JL . A zinc finger protein that represses transcription of the human MHC class II gene, DPA . Journal of Immunology . 156 . 4 . 1448–57 . February 1996 . 10.4049/jimmunol.156.4.1448 . 8568247 . free .
• Coulson JM . Transcriptional regulation: cancer, neurons and the REST . Current Biology . 15 . 17 . R665–8 . September 2005 . 16139198 . 10.1016/j.cub.2005.08.032 . 11901339 . free . 2005CBio...15.R665C .
• Thiel G, Lietz M, Cramer M . 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 . October 1998 . 9756936 . 10.1074/jbc.273.41.26891 . free .
• Andrés ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G . CoREST: a functional corepressor required for regulation of neural-specific gene expression . Proceedings of the National Academy of Sciences of the United States of America . 96 . 17 . 9873–8 . August 1999 . 10449787 . 22303 . 10.1073/pnas.96.17.9873 . 1999PNAS...96.9873A . free .
• Palm K, Metsis M, Timmusk T . 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 . September 1999 . 10521596 . 10.1016/S0169-328X(99)00196-5 .
• Naruse Y, Aoki T, Kojima T, Mori N . Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes . Proceedings of the National Academy of Sciences of the United States of America . 96 . 24 . 13691–6 . November 1999 . 10570134 . 24126 . 10.1073/pnas.96.24.13691 . 1999PNAS...9613691N . free .
• Grimes JA, Nielsen SJ, Battaglioli E, Miska EA, Speh JC, Berry DL, Atouf F, Holdener BC, Mandel G, Kouzarides T . The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex . The Journal of Biological Chemistry . 275 . 13 . 9461–7 . March 2000 . 10734093 . 10.1074/jbc.275.13.9461 . free .
• Coulson JM, Edgson JL, Woll PJ, Quinn JP . 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 . April 2000 . 10766169 .
• Kojima T, Murai K, Naruse Y, Takahashi N, Mori N . Cell-type non-selective transcription of mouse and human genes encoding neural-restrictive silencer factor . Brain Research. Molecular Brain Research . 90 . 2 . 174–86 . June 2001 . 11406295 . 10.1016/S0169-328X(01)00107-3 .
• Battaglioli E, Andrés ME, Rose DW, Chenoweth JG, Rosenfeld MG, Anderson ME, Mandel G . REST repression of neuronal genes requires components of the hSWI.SNF complex . The Journal of Biological Chemistry . 277 . 43 . 41038–45 . October 2002 . 12192000 . 10.1074/jbc.M205691200 . free .
• Lunyak VV, Burgess R, Prefontaine GG, Nelson C, Sze SH, Chenoweth J, Schwartz P, Pevzner PA, Glass C, Mandel G, Rosenfeld MG . Corepressor-dependent silencing of chromosomal regions encoding neuronal genes . Science . 298 . 5599 . 1747–52 . November 2002 . 12399542 . 10.1126/science.1076469 . 2002Sci...298.1747L . 10.1.1.136.7131 . 13507921 .
• Lietz M, Hohl M, Thiel G . RE-1 silencing transcription factor (REST) regulates human synaptophysin gene transcription through an intronic sequence-specific DNA-binding site . European Journal of Biochemistry . 270 . 1 . 2–9 . January 2003 . 12492469 . 10.1046/j.1432-1033.2003.03360.x . free .
• Hersh LB, Shimojo M . Regulation of cholinergic gene expression by the neuron restrictive silencer factor/repressor element-1 silencing transcription factor . Life Sciences . 72 . 18–19 . 2021–8 . March 2003 . 12628452 . 10.1016/S0024-3205(03)00065-1 .
• Kemp DM, Lin JC, Habener JF . Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor . The Journal of Biological Chemistry . 278 . 37 . 35057–62 . September 2003 . 12829700 . 10.1074/jbc.M305891200 . free .
• Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E . Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes . Nature Genetics . 35 . 1 . 76–83 . September 2003 . 12881722 . 10.1038/ng1219 . 28110381 .
• Martin D, Tawadros T, Meylan L, Abderrahmani A, Condorelli DF, Waeber G, Haefliger JA . 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 . December 2003 . 14565956 . 10.1074/jbc.M306861200 . free .
• Kuwahara K, Saito Y, Takano M, Arai Y, Yasuno S, Nakagawa Y, Takahashi N, Adachi Y, Takemura G, Horie M, Miyamoto Y, Morisaki T, Kuratomi S, Noma A, Fujiwara H, Yoshimasa Y, Kinoshita H, Kawakami R, Kishimoto I, Nakanishi M, Usami S, Saito Y, Harada M, Nakao K . NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function . The EMBO Journal . 22 . 23 . 6310–21 . December 2003 . 14633990 . 291842 . 10.1093/emboj/cdg601 .
• Kuwabara T, Hsieh J, Nakashima K, Taira K, Gage FH . A small modulatory dsRNA specifies the fate of adult neural stem cells . Cell . 116 . 6 . 779–93 . March 2004 . 15035981 . 10.1016/S0092-8674(04)00248-X . 12656737 . free .
• Zullo JM, Drake D, Aron L, O'Hern P, Dhamne SC, Davidsohn N, Mao CA, Klein WH, Rotenberg A, Bennett DA, Church GM, Colaiácovo MP, Yankner BA . Regulation of lifespan by neural excitation and REST . Nature . 574 . 7778 . 359–364 . October 2019 . 10.1038/s41586-019-1647-8 . 31619788 . 6893853 . 2019Natur.574..359Z .

Notes and References

1. Web site: Entrez Gene: REST RE1-silencing transcription factor.
2. Schoenherr CJ, Anderson DJ . The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes . Science . 267 . 5202 . 1360–3 . March 1995 . 7871435 . 10.1126/science.7871435 . 1995Sci...267.1360S . 25101475 .
3. Chong JA, Tapia-Ramírez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA, Kraner SD, Mandel G . REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons . Cell . 80 . 6 . 949–57 . March 1995 . 7697725 . 10.1016/0092-8674(95)90298-8 . 6412634 . free .
4. Coulson JM . Transcriptional regulation: cancer, neurons and the REST . Current Biology . 15 . 17 . R665–8 . September 2005 . 16139198 . 10.1016/j.cub.2005.08.032 . 11901339 . free . 2005CBio...15.R665C .
5. Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, Zhao JJ, Roberts TM, Mandel G, Hannon GJ, Depinho RA, Chin L, Elledge SJ . A genetic screen for candidate tumor suppressors identifies REST . Cell . 121 . 6 . 837–48 . June 2005 . 15960972 . 10.1016/j.cell.2005.03.033 . 14082806 . free .
6. Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiácovo MP, Yankner BA . REST and stress resistance in ageing and Alzheimer's disease . Nature . 507 . 7493 . 448–54 . March 2014 . 24670762 . 10.1038/nature13163 . 4110979. 2014Natur.507..448L .
7. Ooi L, Wood IC . Chromatin crosstalk in development and disease: lessons from REST . Nature Reviews Genetics . 8 . 7 . 544–54 . July 2007 . 17572692 . 10.1038/nrg2100 . 415873 .
8. Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS . Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death . Proceedings of the National Academy of Sciences of the United States of America . 109 . 16 . E962–71 . April 2012 . 22371606 . 10.1073/pnas.1121568109 . 3341013. free .
9. Cavadas MA, Mesnieres M, Crifo B, Manresa MC, Selfridge AC, Keogh CE, Fabian Z, Scholz CC, Nolan KA, Rocha LM, Tambuwala MM, Brown S, Wdowicz A, Corbett D, Murphy KJ, Godson C, Cummins EP, Taylor CT, Cheong A . REST is a hypoxia-responsive transcriptional repressor . Scientific Reports . 6 . 31355 . 17 Aug 2016 . 27531581 . 10.1038/srep31355 . 4987654. 2016NatSR...631355C .
10. Andrés ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G . CoREST: a functional corepressor required for regulation of neural-specific gene expression . Proceedings of the National Academy of Sciences of the United States of America . 96 . 17 . 9873–8 . August 1999 . 10449787 . 22303 . 10.1073/pnas.96.17.9873 . 1999PNAS...96.9873A . free .