Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells.
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 regulat...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5328393?pdf=render |
| _version_ | 1818450670354694144 |
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| author | Sanny Moussette Abeer Al Tuwaijri Hamid-Reza Kohan-Ghadr Samar Elzein Raquel Farias Julie Bérubé Bianca Ho Catherine Laprise Cynthia G Goodyer Simon Rousseau Anna K Naumova |
| author_facet | Sanny Moussette Abeer Al Tuwaijri Hamid-Reza Kohan-Ghadr Samar Elzein Raquel Farias Julie Bérubé Bianca Ho Catherine Laprise Cynthia G Goodyer Simon Rousseau Anna K Naumova |
| author_sort | Sanny Moussette |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T20:54:59Z |
| format | Article |
| id | doaj.art-233d149f5aaf4ebd8b8ca868f729fed3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T20:54:59Z |
| publishDate | 2017-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-233d149f5aaf4ebd8b8ca868f729fed32022-12-21T22:47:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01122e017270710.1371/journal.pone.0172707Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells.Sanny MoussetteAbeer Al TuwaijriHamid-Reza Kohan-GhadrSamar ElzeinRaquel FariasJulie BérubéBianca HoCatherine LapriseCynthia G GoodyerSimon RousseauAnna K NaumovaChromosomal 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.http://europepmc.org/articles/PMC5328393?pdf=render |
| spellingShingle | Sanny Moussette Abeer Al Tuwaijri Hamid-Reza Kohan-Ghadr Samar Elzein Raquel Farias Julie Bérubé Bianca Ho Catherine Laprise Cynthia G Goodyer Simon Rousseau Anna K Naumova Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. PLoS ONE |
| title | Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. |
| title_full | Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. |
| title_fullStr | Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. |
| title_full_unstemmed | Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. |
| title_short | Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. |
| title_sort | role of dna methylation in expression control of the ikzf3 gsdma region in human epithelial cells |
| url | http://europepmc.org/articles/PMC5328393?pdf=render |
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