| Project/Area Number |
23659182
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Human genetics
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| Research Institution | Fujita Health University |
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Principal Investigator |
KURAHASHI Hiroki 藤田保健衛生大学, 総合医科学研究所, 教授 (30243215)
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| Project Period (FY) |
2011 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 習慣流産 / アネキシン A5 / グアニン 4 重鎖 / プロモーター / 多型 / 円旋光二色性 / アネキシンA5 / グアニン4重鎖 / 遺伝子多型 / 二次構造 / SNP |
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| Research Abstract |
Recent findings have highlighted the possibility that polymorphismswithin the annexin A5 gene (ANXA5) promoter contribute to the etiology of various obstetriccomplications. However, the underlying mechanisms are unknown. In our present study, thetranscriptional activity of the ANXA5gene promoter was examined in the context of G-quadruplexformation. The M2 haplotype of the promoter polymorphisms that confers a high risk of onset forthese disorders shows lower activity and less expression of ANXA5 mRNA. This gene promoterregion has a motif that potentially forms a G-quadruplex structure, and the M2 allele possesses lesspotential than the major allele. The promoter activity determined by luciferase reporter analysiscorrelated with the in vitro G-quadruplex propensity estimated by circular dichroism. Treatmentwith a G-quadruplex ligand inhibited this promoter activity. Taken together, our data indicate thatthe M2 allele instigates G-quadruplex-mediated transcriptional regulation and consequentlydownregulates the placental anticoagulation factor annexin A5 levels, leading to obstetric disorders.Our data lend support to the developing paradigm that genomic variation affects gene expressionlevels via DNA secondary structures leading to the disease susceptibility.
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