Biology:RE1-silencing transcription factor

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

  • NRSF bound to DNA and cofactors on each of its two cofactor binding domains.

  • 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.[6] 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]

References

  1. ↑ 1.0 1.1 "Entrez Gene: REST RE1-silencing transcription factor". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5978. 
  2. ↑ "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes". Science 267 (5202): 1360–3. March 1995. doi:10.1126/science.7871435. PMID 7871435. Bibcode: 1995Sci...267.1360S. 
  3. ↑ 3.0 3.1 "REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons". Cell 80 (6): 949–57. March 1995. doi:10.1016/0092-8674(95)90298-8. PMID 7697725. 
  4. ↑ "Transcriptional regulation: cancer, neurons and the REST". Current Biology 15 (17): R665–8. September 2005. doi:10.1016/j.cub.2005.08.032. PMID 16139198. 
  5. ↑ "A genetic screen for candidate tumor suppressors identifies REST". Cell 121 (6): 837–48. June 2005. doi:10.1016/j.cell.2005.03.033. PMID 15960972. 
  6. ↑ 6.0 6.1 "REST and stress resistance in ageing and Alzheimer's disease". Nature 507 (7493): 448–54. March 2014. doi:10.1038/nature13163. PMID 24670762. Bibcode: 2014Natur.507..448L. 
  7. ↑ "Chromatin crosstalk in development and disease: lessons from REST". Nature Reviews Genetics 8 (7): 544–54. July 2007. doi:10.1038/nrg2100. PMID 17572692. 
  8. ↑ "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. doi:10.1073/pnas.1121568109. PMID 22371606. 
  9. ↑ "REST is a hypoxia-responsive transcriptional repressor". Scientific Reports 6: 31355. 17 Aug 2016. doi:10.1038/srep31355. PMID 27531581. Bibcode: 2016NatSR...631355C. 
  10. ↑ "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. doi:10.1073/pnas.96.17.9873. PMID 10449787. Bibcode: 1999PNAS...96.9873A. 

Further reading

External links

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



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