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Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells

Moussette Sanny, Al Tuwaijri Abeer Al, Kohan-Ghadr Hamid-Reza, Elzein Samar, Farias Raquel, Bérubé Julie, Ho Bianca, Laprise Catherine, Goodyer Cynthia G., Rousseau Simon et Naumova Anna K.. (2017). Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. PLoS ONE, 12, (2), e0172707.

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URL officielle: http://dx.doi.org/doi:10.1371/journal.pone.0172707

Résumé

Chromosomal region 17q12-q21 is associated with asthma and harbors regulatory polymorphisms that influence expression levels of all five protein-coding genes in the region: IKAROS family zinc finger 3 (Aiolos) (IKZF3), zona pellucida binding protein 2 (ZPBP2), ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3), and gasdermins A and B (GSDMA, GSDMB). Furthermore, DNA methylation in this region has been implicated as a potential modifier of the genetic risk of asthma development. To further characterize the effect of DNA methylation, we examined the impact of treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) that causes DNA demethylation, on expression and promoter methylation of the five 17q12-q21 genes in the human airway epithelium cell line NuLi-1, embryonic kidney epithelium cell line 293T and human adenocarcinoma cell line MCF-7. 5-aza-dC treatment led to upregulation of expression of GSDMA in all three cell lines. ZPBP2 was upregulated in NuLi-1, but remained repressed in 293T and MCF-7 cells, whereas ORMDL3 was upregulated in 293T and MCF-7 cells, but not NuLi-1. Upregulation of ZPBP2 and GSDMA was accompanied by a decrease in promoter methylation. Moreover, 5-aza-dC treatment modified allelic expression of ZPBP2 and ORMDL3 suggesting that different alleles may respond differently to treatment. We also identified a polymorphic CTCF-binding site in intron 1 of ORMDL3 carrying a CG SNP rs4065275 and determined its methylation level. The site's methylation was unaffected by 5-aza-dC treatment in NuLi-1 cells. We conclude that modest changes (8-13%) in promoter methylation levels of ZPBP2 and GSDMA may cause substantial changes in RNA levels and that allelic expression of ZPBP2 and ORMDL3 is mediated by DNA methylation.

Type de document:Article publié dans une revue avec comité d'évaluation
ISSN:1932-6203 (Electronic) 1932-6203 (Linking)
Volume:12
Numéro:2
Pages:e0172707
Version évaluée par les pairs:Oui
Date:2017
Sujets:Sciences de la santé > Sciences médicales > Biologie moléculaire
Sciences de la santé > Sciences médicales > Génétique
Département, module, service et unité de recherche:Départements et modules > Département des sciences fondamentales
Mots-clés:asthma, DNA methylation, gene expression, gene regulation, epithelial cells
Déposé le:05 avr. 2017 20:50
Dernière modification:05 avr. 2017 20:50
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Creative Commons LicenseSauf indication contraire, les documents archivés dans Constellation sont rendus disponibles selon les termes de la licence Creative Commons "Paternité, pas d'utilisation commerciale, pas de modification" 2.5 Canada.

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