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.

最近的研究结果强调了膜联蛋白A5基因（ANXA5）启动子多态性与各种产科并发症的病因有关的可能性。然而，其潜在机制尚不清楚。在我们目前的研究中，anxa5基因启动子的转录活性在g -四层结构的背景下进行了检测。启动子多态性的M2单倍型赋予了这些疾病发病的高风险，显示出较低的活性和较少的anxa5mrna表达。该基因启动子区具有潜在形成g -四重体结构的基序，M2等位基因的潜力小于主等位基因。荧光素酶报告分析确定的启动子活性与圆二色性估计的体外g -四重体倾向相关。用g -四重配体处理可抑制该启动子活性。综上所述，我们的数据表明，M2等位基因激活了g -四重体介导的转录调控，从而下调了胎盘抗凝血因子膜联蛋白A5的水平，从而导致产科疾病。我们的数据支持了基因组变异通过导致疾病易感性的DNA二级结构影响基因表达水平的发展范式。

项目成果

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.

分子遺伝学研究部門

分子遗传学研究部

Lack of Association between Orexin Receptor Genes Polymorphisms and Obstructive Sleep Apnea Syndrome in Japanese

日本人食欲素受体基因多态性与阻塞性睡眠呼吸暂停综合征之间缺乏关联

• 发表时间: 2011
• 期刊: Sleep Biol Rhythms
• 影响因子: 1.1
• 作者: Ahmed WA;Mori T;Nishimura Y;Kitanaka T;Kato T;Bhardwaj KA;Kurahashi H;Suzuki K
• 通讯作者: Suzuki K