The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines
Chemokine receptor CXCR5 is highly expressed in B-cells and under normal conditions is involved in their migration to specific areas of secondary lymphoid organs. B-cells are known to play an important role in various autoimmune diseases including multiple sclerosis (MS) where areas of demyelinating...
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Frontiers Media S.A.
2016-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00515/full |
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doaj-53d355fc9caa4cc0aac2ca21a4435deb2020-11-25T02:19:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-11-01710.3389/fimmu.2016.00515229191The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell linesNikita A Mitkin0Alisa M Muratova1Alisa M Muratova2Anton M Schwartz3Dmitry V Kuprash4Dmitry V Kuprash5Engelhardt Institute of Molecular BiologyEngelhardt Institute of Molecular BiologyLomonosov Moscow State UniversityEngelhardt Institute of Molecular BiologyEngelhardt Institute of Molecular BiologyLomonosov Moscow State UniversityChemokine receptor CXCR5 is highly expressed in B-cells and under normal conditions is involved in their migration to specific areas of secondary lymphoid organs. B-cells are known to play an important role in various autoimmune diseases including multiple sclerosis (MS) where areas of demyelinating lesions attract B-cells by overexpressing CXCL13, the CXCR5 ligand. In this study we aimed to determine the functional significance of single nucleotide polymorphism (SNP) rs630923 (A/C) which is located in cxcr5 gene promoter and its common allele is associated with increased risk of MS. Using bioinformatics and pull-down assay in B-lymphoblastic cell lines, we showed that protective minor rs630923 A allele created functional binding site for MEF2C transcription factor. Elevated MEF2C expression in B-cells correlated with reduced activity of cxcr5 promoter containing rs630923 A allele. This effect that was fully neutralized by MEF2C-directed siRNA may mechanistically explain the protective role of the rs630923 minor allele in MS. Using site-directed mutagenesis of the cxcr5 gene promoter, we were unable to find any experimental evidence for the previously proposed role of NFκB transcription factors in rs630923-mediated CXCR5 promoter regulation. Thus, our results identify MEF2C as a possible mediator of protective function of the rs630923 A allele in MS.http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00515/fullMultiple SclerosisSingle nucleotide polymorphismB-cellsCXCR5rs630923 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Nikita A Mitkin Alisa M Muratova Alisa M Muratova Anton M Schwartz Dmitry V Kuprash Dmitry V Kuprash |
| spellingShingle |
Nikita A Mitkin Alisa M Muratova Alisa M Muratova Anton M Schwartz Dmitry V Kuprash Dmitry V Kuprash The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines Frontiers in Immunology Multiple Sclerosis Single nucleotide polymorphism B-cells CXCR5 rs630923 |
| author_facet |
Nikita A Mitkin Alisa M Muratova Alisa M Muratova Anton M Schwartz Dmitry V Kuprash Dmitry V Kuprash |
| author_sort |
Nikita A Mitkin |
| title |
The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines |
| title_short |
The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines |
| title_full |
The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines |
| title_fullStr |
The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines |
| title_full_unstemmed |
The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced CXCR5 promoter activity in B-cell lymphoblastic cell lines |
| title_sort |
a allele of the single-nucleotide polymorphism rs630923 creates a binding site for mef2c resulting in reduced cxcr5 promoter activity in b-cell lymphoblastic cell lines |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2016-11-01 |
| description |
Chemokine receptor CXCR5 is highly expressed in B-cells and under normal conditions is involved in their migration to specific areas of secondary lymphoid organs. B-cells are known to play an important role in various autoimmune diseases including multiple sclerosis (MS) where areas of demyelinating lesions attract B-cells by overexpressing CXCL13, the CXCR5 ligand. In this study we aimed to determine the functional significance of single nucleotide polymorphism (SNP) rs630923 (A/C) which is located in cxcr5 gene promoter and its common allele is associated with increased risk of MS. Using bioinformatics and pull-down assay in B-lymphoblastic cell lines, we showed that protective minor rs630923 A allele created functional binding site for MEF2C transcription factor. Elevated MEF2C expression in B-cells correlated with reduced activity of cxcr5 promoter containing rs630923 A allele. This effect that was fully neutralized by MEF2C-directed siRNA may mechanistically explain the protective role of the rs630923 minor allele in MS. Using site-directed mutagenesis of the cxcr5 gene promoter, we were unable to find any experimental evidence for the previously proposed role of NFκB transcription factors in rs630923-mediated CXCR5 promoter regulation. Thus, our results identify MEF2C as a possible mediator of protective function of the rs630923 A allele in MS. |
| topic |
Multiple Sclerosis Single nucleotide polymorphism B-cells CXCR5 rs630923 |
| url |
http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00515/full |
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