RE1-silencing transcription factor

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.[5][6][7] REST is expressly involved in the repression of neural genes in non-neuronal cells.[7][8] 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.[9] 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.

REST
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesREST, Rest, 2610008J04Rik, AA407358, NRSF, XBR, REST4, WT6, RE1 silencing transcription factor, GINGF5, HGF5, DFNA27
External IDsOMIM: 600571 MGI: 104897 HomoloGene: 4099 GeneCards: REST
Orthologs
SpeciesHumanMouse
Entrez

5978

19712

Ensembl

ENSG00000084093

ENSMUSG00000029249

UniProt

Q13127

Q8VIG1

RefSeq (mRNA)

NM_001193508
NM_005612
NM_001363453

NM_011263

RefSeq (protein)

NP_001180437
NP_005603
NP_001350382

NP_035393

Location (UCSC)Chr 4: 56.91 – 56.97 MbChr 5: 77.41 – 77.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] REST is found to be down-regulated in elderly people with Alzheimer's disease.[10]

REST contains 8 Cys2His2 zinc fingers and mediates gene repression by recruiting several chromatin-modifying enzymes.[11]

  • NRSF bound to DNA and cofactors on each of its two cofactor binding domains.
    NRSF bound to DNA and cofactors on each of its two cofactor binding domains.
  • Chromatin remodeling occurs, causing the gene to be 'turned off'.
    Chromatin remodeling occurs, causing the gene to be 'turned off'.

REST expression strongly correlates 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.[10] 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.[12] 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.[13]

Interactions

RE1-silencing transcription factor has been shown to interact with RCOR1.[14]

References
  1. GRCh38: Ensembl release 89: ENSG00000084093 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029249 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: REST RE1-silencing transcription factor".
  6. 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. Bibcode:1995Sci...267.1360S. doi:10.1126/science.7871435. PMID 7871435. S2CID 25101475.
  7. 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. PMID 7697725. S2CID 6412634.
  8. Coulson JM (September 2005). "Transcriptional regulation: cancer, neurons and the REST". Current Biology. 15 (17): R665–8. doi:10.1016/j.cub.2005.08.032. PMID 16139198. S2CID 11901339.
  9. 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 (June 2005). "A genetic screen for candidate tumor suppressors identifies REST". Cell. 121 (6): 837–48. doi:10.1016/j.cell.2005.03.033. PMID 15960972. S2CID 14082806.
  10. 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 (March 2014). "REST and stress resistance in ageing and Alzheimer's disease". Nature. 507 (7493): 448–54. Bibcode:2014Natur.507..448L. doi:10.1038/nature13163. PMC 4110979. PMID 24670762.
  11. 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. PMID 17572692. S2CID 415873.
  12. Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS (April 2012). "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. doi:10.1073/pnas.1121568109. PMC 3341013. PMID 22371606.
  13. 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 (17 Aug 2016). "REST is a hypoxia-responsive transcriptional repressor". Scientific Reports. 6: 31355. Bibcode:2016NatSR...631355C. doi:10.1038/srep31355. PMC 4987654. PMID 27531581.
  14. Andrés ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G (August 1999). "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. Bibcode:1999PNAS...96.9873A. doi:10.1073/pnas.96.17.9873. PMC 22303. PMID 10449787.

Further reading

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