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DOI: 10.1055/a-2031-9803
Aberrant Expression of Rest4 Gene in Low-Functioning Pancreatic Beta Cell Line

Abstract
Repressor element-1 silencing transcription factor (Rest) is not expressed in pancreatic beta cells and neuronal cells. However, Rest4, a truncated form of Rest, is expressed in high passaged MIN6 (HP-MIN6) cells, a pancreatic beta cell line that lost glucose-responsive insulin secretion. Rest4 is also expressed in injured MIN6 cells and isolated islets. Herein, the forced expression of dominant negative form of Rest in HP-MIN6 cells was subjected to microarray analysis of gene expression to investigate the role of Rest4 gene in MIN6 cells. Furthermore, the forced expression of Rest4 gene in MIN6 cells was subjected to microarray analysis of gene expression to investigate the function of Rest4 in normal insulin-producing cells. The results showed that Rest4 inhibits cell proliferation and DNA and RNA metabolism and stimulates secretory mechanisms and nervous system gene expression. These findings suggest that Rest4 may act defensively against cellular injury in pancreatic beta cells.
Publication History
Received: 16 December 2022
Accepted: 09 February 2023
Accepted Manuscript online:
09 February 2023
Article published online:
02 March 2023
© 2023. Thieme. All rights reserved.
Georg Thieme Verlag KG
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References
- 1 Martin D, Grapin-Botton A. The importance of REST for development and function of beta cells. Front Cell Dev Biol 2017; 5: 12
- 2 Thiel G, Schuit F. No REST for healthy beta cells. Diabetologia 2008; 51: 1343-1346
- 3 Thiel G, Ekici M, Rössler OG. RE-1 silencing transcription factor (REST): A regulator of neuronal development and neuronal/endocrine function. Cell Tissue Res 2015; 359: 99-109
- 4 Rovira M, Atla G, Maestro MA. et al. REST is a major negative regulator of endocrine differentiation during pancreas organogenesis. Genes Dev 2021; 35: 1229-1242
- 5 Chen ZF, Paquette AJ, Anderson DJ. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nat Genet 1998; 20: 136-142
- 6 Atouf F, Czernichow P, Scharfmann R. Expression of neuronal traits in pancreatic beta cells. Implication of neuron-restrictive silencing factor/repressor element silencing transcription factor, a neuron-restrictive silencer. J Biol Chem 1997; 272: 1929-1934
- 7 Lemaire K, Thorrez L, Schuit F. Disallowed and allowed gene expression: Two faces of mature islet beta cells. Annu Rev Nutr 2016; 36: 45-71
- 8 Hwang J-Y, Zukin RS. REST, a master transcriptional regulator in neurodegenerative disease. Curr Opin Neurobiol 2018; 48: 193-200
- 9 Huang D, Li Q, Wang Y. et al. Brain-specific NRSF deficiency aggravates dopaminergic neurodegeneration and impairs neurogenesis in the MPTP mouse model of Parkinson’s disease. Aging 2019; 11: 3280-3297
- 10 Baldelli P, Meldolesi J. The transcription repressor REST in adult neurons: Physiology, pathology, and diseases. eNeuro 2015; 2: 10-15
- 11 Lu T, Aron L, Zullo J. et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature 2014; 507: 448-454
- 12 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: 76-83
- 13 Chen G-L, Ma Q, Goswami D. et al. Modulation of nuclear REST by alternative splicing: A potential therapeutic target for Huntington’s disease. J Cell Mol Med 2017; 21: 2974-2984
- 14 Spencer EM, Chandler KE, Haddley K. et al. Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models. Neurobiol Dis 2006; 24: 41-52
- 15 Ooi L, Wood IC. Chromatin crosstalk in development and disease: Lessons from REST. Nat Rev Genet 2007; 8: 544-554
- 16 Miyazaki J, Araki K, Yamato E. et al. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: Special reference to expression of glucose transporter isoforms. Endocrinology 1990; 127: 126-132
- 17 Yamato E, Tashiro F, Miyazaki J. Microarray analysis of novel candidate genes responsible for glucose-stimulated insulin secretion in mouse pancreatic β cell line MIN6. PLoS One 2013; 8: e61211
- 18 Yamato E, Noma Y, Tahara Y. et al. Suppression of synthesis and release of glucagon by glucagon-like peptide-1 (7-36 amide) without affect on mRNA level in isolated rat islets. Biochem Biophys Res Commun 1990; 167: 431-437
- 19 Yamato E, Ikegami H, Tahara Y. et al. Cellular mechanism of glyburide-induced insulin gene expression in isolated rat islets. Biochem Biophys Res Commun 1993; 197: 957-964
- 20 Yamato E. High dose of histone deacetylase inhibitors affects insulin secretory mechanism of pancreatic beta cell line. Endocr Regul 2018; 52: 21-26
- 21 Miyazaki S, Tashiro F, Fujikura J. et al. Acinar-to-ductal metaplasia induced by adenovirus-mediated pancreatic expression of Isl1. PLoS One 2012; 7: e47536
- 22 Zhou Y, Zhou B, Pache L. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10: 1523
- 23 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: 843-850
- 24 Ovando-Roche P, Yu JSL, Testori S. et al. TRF2-mediated stabilization of hREST4 is critical for the differentiation and maintenance of neural progenitors. Stem Cells 2014; 32: 2111-2122
- 25 Sugawara H, Tominaga A, Inoue K. et al. Functional characterization of neural-restrictive silencer element in mouse pituitary adenylate cyclase-activating polypeptide (PACAP) gene expression. J Mol Neurosci 2014; 54: 526-534
- 26 Yu M, Cai L, Liang M. et al. Alteration of NRSF expression exacerbating 1-methyl-4-phenyl-pyridinium ion-induced cell death of SH-SY5Y cells. Neurosci Res 2009; 65: 236-244
- 27 Shudo Y, Shimojo M, Fukunaga M. et al. Pituitary adenylate cyclase-activating polypeptide is regulated by alternative splicing of transcriptional repressor REST/NRSF in nerve injury. Life Sci 2015; 143: 174-181
- 28 Chen G-L, Miller GM. Alternative REST splicing underappreciated. eNeuro 2018; 5 ENEURO.0034-18.2018
- 29 Su X-J, Shen B-D, Wang K. et al. Roles of the neuron-restrictive silencer factor in the pathophysiological process of the central nervous system. Front Cell Dev Biol 2022; 10: 834620
- 30 Zhao Y, Zhu M, Yu Y. et al. Brain REST/NRSF is not only a silent repressor but also an active protector. Mol Neurobiol 2017; 54: 541-550
- 31 Arizmendi-Izazaga A, Martínez-Baltazar R, Liborio-Bautista A. et al. The NRSF/REST transcription factor in hallmarks of cancer: From molecular mechanisms to clinical relevance. Biochimie 2023; 206: 116-134
- 32 Marcos-Pérez D, Saenz-Antoñanzas A, Matheu A. Centenarians as models of healthy aging: Example of REST. Ageing Res Rev 2021; 70
- 33 Ghosh I, Liu CS, Swardfager W. et al. The potential roles of excitatory-inhibitory imbalances and the repressor element-1 silencing transcription factor in aging and aging-associated diseases. Mol Cell Neurosci 2021; 117: 103683
- 34 Rocchi A, Carminati E, de Fusco A. et al. REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons. Aging Cell 2021; 20: e13471
- 35 Song Z, Zhao D, Zhao H. et al. NRSF: An angel or a devil in neurogenesis and neurological diseases. J Mol Neurosci 2015; 56: 131-144