RE1-silencing transcription factor

RE1-silencing transcription factor
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2CZY​
Identifiers
Symbols	REST ; NRSF; XBR
External IDs	OMIM: 600571 MGI: 104897 HomoloGene: 4099 GeneCards: REST Gene
Gene ontology Molecular function • core promoter sequence-specific DNA binding • core promoter binding • transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • protein binding • transcription factor binding • outward rectifier potassium channel activity • transcription regulatory region DNA binding • metal ion binding Cellular component • nucleus • nucleoplasm • cytosol • transcriptional repressor complex Biological process • negative regulation of transcription from RNA polymerase II promoter • hematopoietic progenitor cell differentiation • chromatin organization • regulation of transcription, DNA-templated • transcription from RNA polymerase II promoter • negative regulation of cell proliferation • negative regulation of gene expression • negative regulation of aldosterone biosynthetic process • cellular response to drug • positive regulation of apoptotic process • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation by host of viral transcription • negative regulation of neuron differentiation • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • negative regulation of calcium ion-dependent exocytosis • negative regulation of insulin secretion • negative regulation of neurogenesis • cardiac muscle cell myoblast differentiation • histone H4 deacetylation • cellular response to electrical stimulus • cellular response to glucocorticoid stimulus • potassium ion transmembrane transport • negative regulation of cortisol biosynthetic process • negative regulation of dense core granule biogenesis • negative regulation of mesenchymal stem cell differentiation • negative regulation of amniotic stem cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5978	19712
Ensembl	ENSG00000084093	ENSMUSG00000029249
UniProt	Q13127	Q8VIG1
RefSeq (mRNA)	NM_001193508	NM_011263
RefSeq (protein)	NP_001180437	NP_035393
Location (UCSC)	Chr 4: 56.91 – 56.94 Mb	Chr 5: 77.27 – 77.29 Mb
PubMed search

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 ischaemia.

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]

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.^[8]

Interactions

RE1-silencing transcription factor has been shown to interact with RCOR1.^[9]

References

1. "Entrez Gene: REST RE1-silencing transcription factor".
2. 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. PMID 7871435.
3. 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.
4. Coulson J.M. (September 2005). "Transcriptional Regulation: Cancer, Neurons and the REST". Current Biology 15 (17): R665–R668. doi:10.1016/j.cub.2005.08.032.
5. Westbrook TF, Martin ES, Schlabach MR, Leng YM, 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): 837–848. doi:10.1016/j.cell.2005.03.033.
6. Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, X. Shirley; Bennett, David A.; Colaiácovo, Monica P.; Yankner, Bruce A. (2014). "REST and stress resistance in ageing and Alzheimer's disease". Nature. doi:10.1038/nature13163.
7. Ooi L, Wood IC (July 2007). "Chromatin crosstalk in development and disease: lessons from REST". Nat. Rev. Genet. 8 (7): 544–54. doi:10.1038/nrg2100. PMID 17572692.
8. Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, X. Shirley; Bennett, David A.; Colaiácovo, Monica P.; Yankner, Bruce A. (2014). "REST and stress resistance in ageing and Alzheimer's disease". Nature. doi:10.1038/nature13163.
9. 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". Proc. Natl. Acad. Sci. U.S.A. 96 (17): 9873–8. doi:10.1073/pnas.96.17.9873. PMC 22303. PMID 10449787.

Further reading

• 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. PMID 17572692.
• Chong JA, Tapia-Ramírez J, Kim S, et al. (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.
• Schoenherr CJ, Anderson DJ (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. PMID 7871435.
• 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. PMID 8568247.
• Coulson J.M. (September 2005). "Transcriptional Regulation: Cancer, Neurons and the REST". Current Biology 15 (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. PMID 9756936.
• Andrés ME, Burger C, Peral-Rubio MJ, et al. (1999). "CoREST: a functional corepressor required for regulation of neural-specific gene expression.". Proc. Natl. Acad. Sci. U.S.A. 96 (17): 9873–8. doi:10.1073/pnas.96.17.9873. PMC 22303. PMID 10449787.
• 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. PMID 10521596.
• Naruse Y, Aoki T, Kojima T, Mori N (2000). "Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes.". Proc. Natl. Acad. Sci. U.S.A. 96 (24): 13691–6. doi:10.1073/pnas.96.24.13691. PMC 24126. PMID 10570134.
• 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. PMID 10734093.
• 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. PMID 10766169.
• 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. PMID 11406295.
• 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. PMID 12192000.
• Lunyak VV, Burgess R, Prefontaine GG, et al. (2002). "Corepressor-dependent silencing of chromosomal regions encoding neuronal genes.". Science 298 (5599): 1747–52. doi:10.1126/science.1076469. PMID 12399542.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• 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. PMID 12492469.
• 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. PMID 12628452.
• 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. PMID 12829700.
• 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. PMID 12881722.
• 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. PMID 14565956.
• Kuwahara K, Saito Y, Takano M, et al. (2004). "NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function". EMBO J. 22 (23): 6310–21. doi:10.1093/emboj/cdg601. PMC 291842. PMID 14633990.
• Kuwabara T, Hsieh J, Nakashima K, et al. (2004). "A small modulatory dsRNA specifies the fate of adult neural stem cells". Cell 116 (6): 779–93. doi:10.1016/S0092-8674(04)00248-X. PMID 15035981.

External links

• REST protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook NRSF

This article incorporates text from the United States National Library of Medicine, which is in the public domain.