RE1-silencing transcription factor

Last updated
REST
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases REST , Rest, 2610008J04Rik, AA407358, NRSF, XBR, REST4, WT6, RE1 silencing transcription factor, GINGF5, HGF5, DFNA27
External IDs OMIM: 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 Mb Chr 5: 77.41 – 77.43 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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]

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]

Related Research Articles

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

<span class="mw-page-title-main">HHV Infected Cell Polypeptide 0</span> Protein

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate-early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.

<span class="mw-page-title-main">Protein c-Fos</span> Mammalian protein found in Homo sapiens

Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

<span class="mw-page-title-main">SIN3A</span> Protein-coding gene in the species Homo sapiens

Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.

<span class="mw-page-title-main">ATF3</span> Protein-coding gene in the species Homo sapiens

Cyclic AMP-dependent transcription factor ATF-3 is a protein that, in humans, is encoded by the ATF3 gene.

<span class="mw-page-title-main">HDAC9</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.

<span class="mw-page-title-main">HES1</span> Protein-coding gene in the species Homo sapiens

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

<span class="mw-page-title-main">RCOR1</span> Protein-coding gene in the species Homo sapiens

REST corepressor 1 also known as CoREST is a protein that in humans is encoded by the RCOR1 gene.

<span class="mw-page-title-main">OLIG2</span> Protein-coding gene in the species Homo sapiens

Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix (bHLH) transcription factor encoded by the OLIG2 gene. The protein is of 329 amino acids in length, 32 kDa in size and contains one basic helix-loop-helix DNA-binding domain. It is one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in central nervous system, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining motor neuron and oligodendrocyte differentiation, as well as its role in sustaining replication in early development. It is mainly involved in diseases such as brain tumor and Down syndrome.

<span class="mw-page-title-main">SIN3B</span> Protein-coding gene in the species Homo sapiens

Paired amphipathic helix protein Sin3b is a protein that in humans is encoded by the SIN3B gene.

Neurogenins, often abbreviated as Ngn, are a family of bHLH transcription factors involved in specifying neuronal differentiation. The family consisting of Neurogenin-1, Neurogenin-2, and Neurogenin-3, plays a fundamental role in specifying neural precursor cells and regulating the differentiation of neurons during embryonic development. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.

<span class="mw-page-title-main">ZNF238</span> Protein-coding gene in humans

Zinc finger protein 238 is a zinc finger containing transcription factor that in humans is encoded by the ZNF238 gene.

<span class="mw-page-title-main">PHF21A</span> Protein-coding gene in the species Homo sapiens

PHD finger protein 21A is a protein that in humans is encoded by the PHF21A gene.

<span class="mw-page-title-main">TBR1</span> Protein-coding gene in Homo sapiens

T-box, brain, 1 is a transcription factor protein important in vertebrate embryo development. It is encoded by the TBR1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978. TBR1 is a member of the TBR1 subfamily of T-box family transcription factors, which share a common DNA-binding domain. Other members of the TBR1 subfamily include EOMES and TBX21. TBR1 is involved in the differentiation and migration of neurons and is required for normal brain development. TBR1 interacts with various genes and proteins in order to regulate cortical development, specifically within layer VI of the developing six-layered human cortex. Studies show that TBR1 may play a role in major neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and autism spectrum disorder (ASD).

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.

<span class="mw-page-title-main">PRICKLE1</span> Protein-coding gene in the species Homo sapiens

Prickle planar cell polarity protein 1 is a protein that in humans is encoded by the PRICKLE1 gene.

Lezanne Ooi is an Australian neuroscientist who is Professor and Head of Neurodevelopment at the University of Wollongong. Her research considers the development of cellular imaging techniques to understand neurodegenerative disease.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000084093 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "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. 1 2 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. 1 2 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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