Generic placeholder image

Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Genome-wide Association Studies of REST Gene Associated Neurological Diseases/traits with Related Single Nucleotide Polymorphisms

Author(s): Jingjing Wang, Sagor Kumar Roy, Seidu A. Richard and Yuming Xu*

Volume 20, Issue 3, 2023

Published on: 22 August, 2023

Page: [410 - 422] Pages: 13

DOI: 10.2174/1567202620666230727153306

open access plus


Background: Genome-wide association studies (GWAS) have been used to explore the connections between genotypes and phenotypes by comparing the genotype frequencies of genetic changes in individuals with similar origins but distinct traits.

Objectives: The aim is to employ the GWAS catalog to identify and investigate the various correlations between genotypes and phenotypes of the REST gene.

Methods: In this study, we utilized a large dataset of GWAS comprising 62,218,976 individuals in 112 studies and 122 associations with 122 traits ( from European, Asian, Hispanic, African ancestry up to 28 February 2023. Protein-association network evaluation and gene ontology enrichment study was utilized to evaluate the biological function of the discovered gene modules.

Results: We identified several associations for both neurodevelopmental and neurodegenerative disorders linked to REST, as well as its mapped gene modules and their functional relationship networks.

Conclusion: This work offers fresh insights into identifying risk loci of neurological disorders caused by REST.

Keywords: GWAS, REST, NRSF, ADHD, cognitive dysfunction, migraine disorder.

Visscher PM, Wray NR, Zhang Q, et al. 10 Years of gwas discovery: Biology, function, and translation. Am J Hum Genet 2017; 101(1): 5-22.
[] [PMID: 28686856]
Benjamin DJ, Cesarini D, Chabris CF, et al. The promises and pitfalls of genoeconomics. Annu Rev Econ 2012; 4(1): 627-62.
[] [PMID: 23482589]
Chong JA, Tapia-Ramírez J, Kim S, et al. REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 1995; 80(6): 949-57.
[] [PMID: 7697725]
Schoenherr CJ, Paquette AJ, Anderson DJ. Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci 1996; 93(18): 9881-6.
[] [PMID: 8790425]
Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 2005; 121(4): 645-57.
[] [PMID: 15907476]
Gao Z, Ure K, Ding P, et al. The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci 2011; 31(26): 9772-86.
[] [PMID: 21715642]
Wu J, Xie X. Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol 2006; 7(9): R85.
[] [PMID: 17002790]
Johnson R, Teh CH, Kunarso G, et al. REST regulates distinct transcriptional networks in embryonic and neural stem cells. PLoS Biol 2008; 6(10): e256.
[] [PMID: 18959480]
McClelland S, Brennan GP, Dubé C, et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. eLife 2014; 3e01267.
[] [PMID: 25117540]
Huang Y, Myers SJ, Dingledine R. Transcriptional repression by rest: Recruitment of Sin3A and histone deacetylase to neuronal genes. Nat Neurosci 1999; 2(10): 867-72.
[] [PMID: 10491605]
Ballas N, Mandel G. The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol 2005; 15(5): 500-6.
[] [PMID: 16150588]
Ooi L, Wood IC. Chromatin crosstalk in development and disease: Lessons from REST. Nat Rev Genet 2007; 8(7): 544-54.
[] [PMID: 17572692]
Stahl EA, Raychaudhuri S, Remmers EF, et al. Genome: Wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 2010; 42(6): 508-14.
[] [PMID: 20453842]
Narlikar L, Ovcharenko I. Identifying regulatory elements in eukaryotic genomes. Brief Funct Genomics Proteomics 2009; 8(4): 215-30.
[] [PMID: 19498043]
Karlsson Linnér R, Mallard TT, Barr PB, et al. Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. Nat Neurosci 2021; 24(10): 1367-76.
[] [PMID: 34446935]
Yeh PK, Liang CS, Tsai CL, et al. Genetic variants associated with subjective cognitive decline in patients with migraine. Front Aging Neurosci 2022; 14860604.
[] [PMID: 35783123]
Bruce AW, Donaldson IJ, Wood IC, et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc Natl Acad Sci 2004; 101(28): 10458-63.
[] [PMID: 15240883]
Mortazavi A, Thompson ECL, Garcia ST, Myers RM, Wold B. Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoire. Genome Res 2006; 16(10): 1208-21.
[] [PMID: 16963704]
Johnson DS, Mortazavi A, Myers RM, Wold B. Genome-wide mapping of in vivo protein-DNA interactions. Science 2007; 316(5830): 1497-502.
[] [PMID: 17540862]
Schoenherr CJ, Anderson DJ. The neuron-restrictive silencer factor (NRSF): A coordinate repressor of multiple neuron-specific genes. Science 1995; 267(5202): 1360-3.
[] [PMID: 7871435]
Tapia-Ramírez J, Eggen BJL, Peral-Rubio MJ, Toledo-Aral JJ, Mandel G. A single zinc finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter. Proc Natl Acad Sci 1997; 94(4): 1177-82.
[] [PMID: 9037026]
Jothi R, Cuddapah S, Barski A, Cui K, Zhao K. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 2008; 36(16): 5221-31.
[] [PMID: 18684996]
Miller J, McLachlan AD, Klug A. Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO J 1985; 4(6): 1609-14.
[] [PMID: 4040853]
Bellefroid EJ, Marine JC, Ried T, et al. Clustered organization of homologous KRAB zinc-finger genes with enhanced expression in human T lymphoid cells. EMBO J 1993; 12(4): 1363-74.
[] [PMID: 8467795]
Najafabadi HS, Mnaimneh S, Schmitges FW, et al. C2H2 zinc finger proteins greatly expand the human regulatory lexicon. Nat Biotechnol 2015; 33(5): 555-62.
[] [PMID: 25690854]
Sun YM, Greenway DJ, Johnson R, et al. Distinct profiles of REST interactions with its target genes at different stages of neuronal development. Mol Biol Cell 2005; 16(12): 5630-8.
[] [PMID: 16195345]
Johnson R, Teh CHL, Jia H, et al. Regulation of neural macroRNAs by the transcriptional repressor REST. RNA 2009; 15(1): 85-96.
[] [PMID: 19050060]
Jobe EM, McQuate AL, Zhao X. Crosstalk among epigenetic pathways regulates neurogenesis. Front Neurosci 2012; 6: 59.
[] [PMID: 22586361]
Willert J, Epping M, Pollack JR, Brown PO, Nusse R. A transcriptional response to Wnt protein in human embryonic carcinoma cells. BMC Dev Biol 2002; 2(1): 8.
[] [PMID: 12095419]
Nishihara S, Tsuda L, Ogura T. The canonical Wnt pathway directly regulates NRSF/REST expression in chick spinal cord. Biochem Biophys Res Commun 2003; 311(1): 55-63.
[] [PMID: 14575694]
Paquette AJ, Perez SE, Anderson DJ. Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc Natl Acad Sci 2000; 97(22): 12318-23.
[] [PMID: 11050251]
Aoki H, Hara A, Era T, Kunisada T, Yamada Y. Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis. Development 2012; 139(4): 667-77.
[] [PMID: 22241837]
Prada I, Marchaland J, Podini P, et al. REST/NRSF governs the expression of dense-core vesicle gliosecretion in astrocytes. J Cell Biol 2011; 193(3): 537-49.
[] [PMID: 21536750]
Moreno-González G, López-Colomé AM, Rodríguez G, Zarain-Herzberg A. Transcription of the chicken Grin1 gene is regulated by the activity of SP3 and NRSF in undifferentiated cells and neurons. Biosci Rep 2008; 28(4): 177-88.
[] [PMID: 18557703]
Yuan Y, Chow BKC, Lee VHY, Lee LTO. Neuron-restrictive silencer factor functions to suppress Sp1-mediated transactivation of human secretin receptor gene. Biochim Biophys Acta Gene Regul Mech 2013; 1829(2): 231-8.
[] [PMID: 23168245]
Bersten DC, Wright JA, McCarthy PJ, Whitelaw ML. Regulation of the neuronal transcription factor NPAS4 by REST and microRNAs. Biochim Biophys Acta Gene Regul Mech 2014; 1839(1): 13-24.
[] [PMID: 24291638]
D’Alessandro R, Klajn A, Meldolesi J. Expression of dense-core vesicles and of their exocytosis are governed by the repressive transcription factor NRSF/REST. Ann N Y Acad Sci 2009; 1152(1): 194-200.
[] [PMID: 19161390]
Paonessa F, Latifi S, Scarongella H, Cesca F, Benfenati F. Specificity protein 1 (Sp1)-dependent activation of the synapsin I gene (SYN1) is modulated by RE1-silencing transcription factor (REST) and 5′-cytosine-phosphoguanine (CpG) methylation. J Biol Chem 2013; 288(5): 3227-39.
[] [PMID: 23250796]
Shimojo M. Characterization of the nuclear targeting signal of REST/NRSF. Neurosci Lett 2006; 398(3): 161-6.
[] [PMID: 16442230]
Zuccato C, Tartari M, Crotti A, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003; 35(1): 76-83.
[] [PMID: 12881722]
Lu T, Aron L, Zullo J, et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature 2014; 507(7493): 448-54.
[] [PMID: 24670762]
Raj B, O’Hanlon D, Vessey JP, et al. Cross-regulation between an alternative splicing activator and a transcription repressor controls neurogenesis. Mol Cell 2011; 43(5): 843-50.
[] [PMID: 21884984]

© 2023 Bentham Science Publishers | Privacy Policy