Recurrent pregnancy loss -associated promoter polymorphisms affect ANXA5 ge ne expression via G -quadruplex propensity

复发性流产相关启动子多态性通过G四链体倾向影响ANXA5基因表达

• 批准号: 23659182
• 负责人: KURAHASHI Hiroki
• 金额: $ 2.41万
• 依托单位: Fujita Health University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-23659182/
• 关键词: 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

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.

最近的发现强调了膜联蛋白A5基因（ANXA5）启动子促进构成各种产科综述的病因的可能性。但是，基本机制尚不清楚。在我们目前的研究中，在G-四链体形式的背景下检查了Anxa5gene启动子的三个文字活性。启动子多态性的M2单倍型赋予了高发性疾病的高风险，其活性较低，而Anxa5 mRNA的表达则较低。该基因启动区的基序有可能形成g四链体结构，而M2等位基因比主要等位基因具有较小的电势。通过荧光素酶报道器分析确定的启动子活性与通过圆形二色性估计的体外G-四链体倾向相关。治疗与G四链体配体抑制了该启动子活性。 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.

项目成果

Mechanism of complex gross chromosomal rearrangements : A commentary on Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation

复杂的染色体重排机制：严重精神发育迟滞男性患者MECP2和ATRX同时微重复的评论

• DOI: 10.1038/jhg.2011.143
• 发表时间: 2012
• 期刊: J Hum Genet
• 影响因子: 3.5
• 作者: Kurahashi H;Ohye T;Inagaki H;Kogo H;Tsutsumi M
• 通讯作者: Tsutsumi M

HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes

• DOI: 10.1111/j.1365-2443.2012.01600.x
• 发表时间: 2012-06-01
• 期刊: GENES TO CELLS
• 影响因子: 2.1
• 作者: Kogo, Hiroshi;Tsutsumi, Makiko;Kurahashi, Hiroki
• 通讯作者: Kurahashi, Hiroki

Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient

胞质分裂 8 (DOCK8) 缺陷患者发生急性嗜酸细胞性肺炎

• 发表时间: 2013
• 期刊: Pediatric Pulmonology
• 影响因子: 3.1
• 作者: Tsuge I;Ito K;Ohye T;Kando N;Kondo Y;Nakajima Y;Inuo C;Kurahashi H;Urisu A
• 通讯作者: Urisu A

A Functional variation in the hypocretin...

下丘脑分泌素的功能变异...

• 发表时间: 2012
• 期刊: Laryngoscope
• 影响因子: 2.6
• 作者: Ahmed WA;Tsutsumi M;Nakata S;et al.
• 通讯作者: et al.

Polymorphisms in the annexin A5 gene promoter...

膜联蛋白 A5 基因启动子的多态性...

• 发表时间: 2011
• 作者: Kurahashi H;Miyamura H;Nishizawa H;et al.
• 通讯作者: et al.