REST and the RESTless: in Stem Cells and Beyond

Overview

Journal Future Neurol

Specialty Neurology

Date 2009 Nov 4

PMID 19885378

Citations 37

Authors

Vidya Gopalakrishnan

Affiliations

Soon will be listed here.

Abstract

Since its original discovery as a negative regulator of neuronal differentiation, the repressor element (RE)-1 silencing transcription factor (REST), also known as the neuron-restrictive silencer factor, has been implicated in novel processes such as maintenance of embryonic stem cell pluripotency and self-renewal and regulation of mitotic fidelity in non-neural cells. REST expression and activity is tightly controlled by transcriptional and post-transcriptional mechanisms in a cell and developmental stage-specific manner and perturbations in its levels or function are associated with various pathological states. REST differentially influences target-gene expression through interaction with a wide variety of cellular cofactors in a context-dependent manner. However, the influence of the microenvironment on REST-mediated regulation of gene expression is poorly understood. This review will present our current understanding of REST signaling with a greater focus on its emerging ties with noncoding RNAs and novel interacting partners, as well as its roles in embryonic stem cell self-renewal, cellular plasticity and oncogenesis/tumor suppression.

Citing Articles

REST Is Restless in Neuronal and Non-Neuronal Virus Infections: An In Silico Analysis-Based Perspective.

Pillai V, Ravindran S, Krishna G, Abhinand C, Nelson-Sathi S, Veettil M Viruses. 2025; 17(2).

PMID: 40006989 PMC: 11860772. DOI: 10.3390/v17020234.

Massively parallel characterization of transcriptional regulatory elements.

Agarwal V, Inoue F, Schubach M, Penzar D, Martin B, Dash P Nature. 2025; 639(8054):411-420.

PMID: 39814889 PMC: 11903340. DOI: 10.1038/s41586-024-08430-9.

Endotype Characterization Reveals Mechanistic Differences Across Brain Regions in Sporadic Alzheimer's Disease.

Patel A, Caldwell A, Ramachandran S, Subramaniam S J Alzheimers Dis Rep. 2023; 7(1):957-972.

PMID: 37849634 PMC: 10578327. DOI: 10.3233/ADR-220098.

Zebrafish as a model organism for neurodegenerative disease.

Chia K, Klingseisen A, Sieger D, Priller J Front Mol Neurosci. 2022; 15:940484.

PMID: 36311026 PMC: 9606821. DOI: 10.3389/fnmol.2022.940484.

Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression.

Cloud A, Vargheese A, Gunewardena S, Shimak R, Ganeshkumar S, Kumaraswamy E BMC Cancer. 2022; 22(1):180.

PMID: 35177031 PMC: 8851790. DOI: 10.1186/s12885-022-09280-2.

References

Leone S, Mutti C, Kazantsev A, Sturlese M, Moro S, Cattaneo E . SAR and QSAR study on 2-aminothiazole derivatives, modulators of transcriptional repression in Huntington's disease. Bioorg Med Chem. 2008; 16(10):5695-703. DOI: 10.1016/j.bmc.2008.03.067. View

Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K . Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008; 321(5889):699-702. DOI: 10.1126/science.1154884. View

Su X, Kameoka S, Lentz S, Majumder S . Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation. Mol Cell Biol. 2004; 24(18):8018-25. PMC: 515039. DOI: 10.1128/MCB.24.18.8018-8025.2004. View

Bassuk A, Wallace R, Buhr A, Buller A, Afawi Z, Shimojo M . A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet. 2008; 83(5):572-81. PMC: 2668041. DOI: 10.1016/j.ajhg.2008.10.003. View

Majumder S . REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell Cycle. 2006; 5(17):1929-35. DOI: 10.4161/cc.5.17.2982. View

Su X, Gopalakrishnan V, Stearns D, Aldape K, Lang F, Fuller G . Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Mol Cell Biol. 2006; 26(5):1666-78. PMC: 1430235. DOI: 10.1128/MCB.26.5.1666-1678.2006. View

Shimojo M . Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150 Glued. J Biol Chem. 2008; 283(50):34880-6. PMC: 2596380. DOI: 10.1074/jbc.M804183200. View

Watanabe Y, Kameoka S, Gopalakrishnan V, Aldape K, Pan Z, Lang F . Conversion of myoblasts to physiologically active neuronal phenotype. Genes Dev. 2004; 18(8):889-900. PMC: 395848. DOI: 10.1101/gad.1179004. View

Chong J, Tapia-Ramirez J, Kim S, Toledo-Aral J, Zheng Y, Boutros M . REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell. 1995; 80(6):949-57. DOI: 10.1016/0092-8674(95)90298-8. View

10.

Carter M, Stagg C, Falco G, Yoshikawa T, Bassey U, Aiba K . An in situ hybridization-based screen for heterogeneously expressed genes in mouse ES cells. Gene Expr Patterns. 2008; 8(3):181-98. PMC: 2238805. DOI: 10.1016/j.gep.2007.10.009. View

11.

Fuller G, Su X, Price R, Cohen Z, Lang F, Sawaya R . Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16. Mol Cancer Ther. 2005; 4(3):343-9. DOI: 10.1158/1535-7163.MCT-04-0228. View

12.

Barrachina M, Moreno J, Juves S, Moreno D, Olive M, Ferrer I . Target genes of neuron-restrictive silencer factor are abnormally up-regulated in human myotilinopathy. Am J Pathol. 2007; 171(4):1312-23. PMC: 1988880. DOI: 10.2353/ajpath.2007.070520. View

13.

Johnson R, Zuccato C, Belyaev N, Guest D, Cattaneo E, Buckley N . A microRNA-based gene dysregulation pathway in Huntington's disease. Neurobiol Dis. 2007; 29(3):438-45. DOI: 10.1016/j.nbd.2007.11.001. View

14.

Coulson J . Transcriptional regulation: cancer, neurons and the REST. Curr Biol. 2005; 15(17):R665-8. DOI: 10.1016/j.cub.2005.08.032. View

15.

Kuratomi S, Kuratomi A, Kuwahara K, Ishii T, Nakao K, Saito Y . NRSF regulates the developmental and hypertrophic changes of HCN4 transcription in rat cardiac myocytes. Biochem Biophys Res Commun. 2006; 353(1):67-73. DOI: 10.1016/j.bbrc.2006.11.119. View

16.

Calderone A, Jover T, Noh K, Tanaka H, Yokota H, Lin Y . Ischemic insults derepress the gene silencer REST in neurons destined to die. J Neurosci. 2003; 23(6):2112-21. PMC: 6741998. View

17.

Jaenisch R, Young R . Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008; 132(4):567-82. PMC: 4142810. DOI: 10.1016/j.cell.2008.01.015. View

18.

Hermanson O . Stem cells have different needs for REST. PLoS Biol. 2008; 6(10):e271. PMC: 2573942. DOI: 10.1371/journal.pbio.0060271. View

19.

Johnson R, Gamblin R, Ooi L, Bruce A, Donaldson I, Westhead D . Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication. Nucleic Acids Res. 2006; 34(14):3862-77. PMC: 1557810. DOI: 10.1093/nar/gkl525. View

20.

Ballas N, Mandel G . The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol. 2005; 15(5):500-6. DOI: 10.1016/j.conb.2005.08.015. View