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

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659182
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: Fujita Health University
• Principal Investigator: KURAHASHI Hiroki 藤田保健衛生大学, 総合医科学研究所, 教授 (30243215)
• Project Period (FY): 2011 – 2012
• 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

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.

Research Products

• [Journal Article] Two sequential cleavage reactions on cruciform DNA structures cause palindrome -mediated chromosomal translocations (2013)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
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  • DOI: doi:10.1038/ncomms2595
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• [Journal Article] MTA3 regulates CGB5 and Snail genes in trophoblast (2013)
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• [Journal Article] Chromosomal translocations and palindromic AT-rich repeats (2012)
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• [Journal Article] HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes (2012)
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• [Journal Article] HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity (2012)
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  • Journal Title: Genes Cells Volume: 17 Pages: 897-912
  • DOI: doi:10.1111/gtc.12005.
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• [Journal Article] Failure of homologous synapsis and sex-specific reproduction problems (2012)
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• [Journal Article] Molecular basis of maternal age-related increase in oocyte aneuploidy (2012)
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  • Journal Title: Congenit Anom (Kyoto) Volume: 52 Pages: 8-15
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• [Journal Article] Mechanism of complex gross chromosomal rearrangements: A commentary on Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation. (2012)
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• [Journal Article] Screening of genes involved in chromosome segregation during meiosis I: in vitro gene transfer to mouse fetal oocytes. (2012)
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• [Journal Article] Kurahashi H, Udagawa Y. Upregulation of HtrA4 in the placentas of patients with severe pre-eclampsia (2012)
  • Author(s): Inagaki A, Nishizawa H, Ota S, Suzuki M, Inuzuka H, Miyamura H, Sekiya T
  • Journal Title: Placenta Volume: 33 Pages: 919-26
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• [Journal Article] Serum neutrophil gelatinase-associated lipocalin during the early postoperative period predicts the recovery of graft function after kidney transplantation from donors after cardiac death (2012)
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  • Journal Title: J Urol Volume: 187 Pages: 2261-2267
  • DOI: doi:10.1016/j.juro.2012.01.033.
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• [Journal Article] A Functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan (2012)
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  • Journal Title: Laryngoscope Volume: 122 Pages: 925-929
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• [Journal Article] Global gene expression profiling in PPAR-γ agonist-treated kidneys in an orthologous rat model of human autosomal recessive polycystic kidney disease (2012)
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  • Journal Title: PPAR Research Pages: 695898
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• [Journal Article] DNA secondary structure is influenced by genetic variation and alters susceptibility to de novo translocation (2011)
  • Author(s): Kato T, Inagaki H, Tong M, Kogo H, Ohye T, Yamada K, Tsutsumi M, Emanuel BS,Kurahashi H.
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• [Journal Article] Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
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  • Journal Title: Nature Volume: 478 Pages: 127-131
  • DOI: doi:10.1038/nature10456
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• [Journal Article] Characterization of a novel mouse gene encoding an SYCP3-like protein that re-localizes from the XY body to the nucleolus during prophase of male meiosis I (2011)
  • Author(s): Tsutsumi M, Kogo H, Kowa-Sugiyama H, Inagaki H, Ohye T, Kurahashi H.
  • Journal Title: Biol Reprod Volume: 85 Pages: 165-171
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• [Journal Article] Polymorphism in annexin A5 gene promoter in Japanese women with recurrent pregnancy loss (2011)
  • Author(s): Miyamura H, Nishizawa H, Ota S, Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kato T, Pryor-Koishi K, Nakanishi I, Fujita T, Imayoshi Y, Markoff A, Yanagihara I, Udagawa Y, Kurahashi H
  • Journal Title: Mol Hum Reprod Volume: 17 Pages: 447-452
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• [Journal Article] A rare synaptonemal complex protein 3 gene varian in unexplained female infertility (2011)
  • Author(s): Nishiyama S, Kishi T, Kato T, Suzuki M, Bolor H, Udagawa Y, Kurahashi H.
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• [Journal Article] Comparative gene expression profiling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction. (2011)
  • Author(s): Nishizawa H, Ota S, Suzuki M, Kato T, Sekiya T, Kurahashi H, Udagawa Y
  • Journal Title: Reprod Biol Endocrinol Volume: 9 Pages: 107
  • DOI: doi:10.1186/1477-7827-9-107
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• [Journal Article] Impact of indoleamine 2,3-dioxygenase on the antioxidant system in the placentas of severely pre-eclamptic patients (2011)
  • Author(s): Nishizawa H, Suzuki M, Pryor-Koishi K,Sekiya T, Tada S, Kurahashi H, Udagawa Y
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• [Journal Article] Global gene expression profiling in early-stage polycystic kidney disease in the Han : SPRD Cy rat identifies a role for RXR signaling (2011)
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  • Journal Title: Am J Physiol Renal Physiol Volume: 300 Pages: F177-88
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• [Journal Article] PPAR-{gamma} agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. (2011)
  • Author(s): Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, Yamaguchi T,Calvet JP, Wallace DP, Nagao S
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• [Journal Article] Lack of Association between Orexin Receptor Genes Polymorphisms and Obstructive Sleep Apnea Syndrome in Japanese (2011)
  • Author(s): Ahmed WA, Mori T, Nishimura Y, Kitanaka T, Kato T, Bhardwaj KA, Kurahashi H, Suzuki K.
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• [Journal Article] Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient.
  • Author(s): Tsuge I, Ito K, Ohye T, Kando N, Kondo Y, Nakajima Y, Inuo C, Kurahashi H, Urisu A.
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• [Presentation] Pathogenic exon-trapping by SVA retrotransposon and rescue in Faukuyama muscular dystrophy (2012)
  • Author(s): Taniguchi M, Kobayashi K, Kanagawa M, Yu CC, Oda T, Kuga A, Kurahashi H, Akmen HO,DiMauro S, Yokota T, Takeda S, Toda T
  • Organizer: ASHG 2012, annual meeting
  • Place of Presentation: San Francisco
  • Year and Date: 20121106-10
• [Presentation] Obstetric complication-associated ANXA5promoter polymorphisms affect gene expression via DNA secondary structures (2012)
  • Author(s): Inagaki H, Ota S, Nishizawa H, Miyamura H, Nakahira K, Suzuki M, Nishiyama S, Udagawa Y, Yanagihara I, Kurahashi H.
  • Organizer: ASHG 2012, annual meeting
  • Place of Presentation: San Francisco
  • Year and Date: 20121106-10
• [Presentation] Polymorphisms in the ANXA5gene promoter in Japanese women with preeclampsia (2012)
  • Author(s): Miyamura H, Nishizawa H, Ota S,Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kurahashi H, Udagawa Y.
  • Organizer: The XX FIGO World Congress
  • Place of Presentation: Rome, Italy
  • Year and Date: 20121007-12
• [Presentation] Mechanism of recurrent translocation t(11;22) initiated by cruciform conformation of palindromes (2012)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kurahashi H.
  • Organizer: FASEB SRC:"Dynamic DNA structures in biology
  • Place of Presentation: Saxtons River, USA
  • Year and Date: 20120617-22
• [Presentation] Mechanism of recurrent translocation t(11;22) initiated by cruciform conformation of palindromic sequences (2011)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H.
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal,Canada
  • Year and Date: 20111011-15
• [Presentation] Identification of a novel palindrome mediated translocation associated with the t(3;8) of hereditary renal cancer (2011)
  • Author(s): Kato T, Sheridan MB, Hacker AM, Inagaki H, Glover TW, Plon SE, Drabkin HA, Gemmill RM, Kurahashi H, Emanuel BS
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] Identification of a recombination hotspot sequence at the breakpoint region of the 22q11 deletion using a yeast model (2011)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Emanuel BS, Kurahashi H.
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal,Canada
  • Year and Date: 20111011-15
• [Presentation] HORMAD1-deficiency causes azoospermia in males and pregnancy loss in females (2011)
  • Author(s): Kogo H, Tsutsumi M, Ohye T, Inagaki H,Kurahashi H.
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] Mutation in the SYCP3 gene identified in a woman with recurrent pregnancy loss affect the synaptonemal complex conformation at meiotic prophase I (2011)
  • Author(s): Tsutsumi M, Kogo H, Inagaki H, Ohye T,Kurahashi H.
  • Organizer: The 12th International Congress of Human Genetics, Montreal
  • Place of Presentation: Canada
  • Year and Date: 20111011-15
• [Presentation] Polymorphisms in the ANXA5gene promoter in Japanese women with pre-eclampsia (2011)
  • Author(s): Kurahashi H, Miyamura H, Nishizawa H, Ota S,Suzuki M, Inagaki A, Egusa H, Nishiyama S, Udagawa Y.
  • Organizer: European Society of Human Genetics Conference 2012.
  • Place of Presentation: Nurnberg,Germany
  • Year and Date: 20110623-26
• [Presentation] Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss (2011)
  • Author(s): Miyamura H, Nishizawa H, Ota S, Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kato T, Pryor-Koishi K, Nakanishi I, Fujita T,Imayoshi Y, Markoff A, Yanagihara I,Udagawa Y, Kurahashi H.
  • Organizer: 27th Annual Meeting of ESHRE - Stockholm 2011
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 20110603-06
• [Presentation] Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss (2011)
  • Author(s): Kurahashi H, Miyamura H, Nishizawa H, Ota S, Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kato T, Pryor-Koishi K, Nakanishi I, Fujita T, Imayoshi Y, Negi R, Markoff A, Yanagihara I, Udagawa, Y.
  • Organizer: European Society of Human Genetics Conference 2011.
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 20110528-31
• [Presentation] Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss (2011)
  • Author(s): Miyamura H, Nishizawa H, Ota S, Suzuki M, Inagaki A, Egusa H, Nishiyama S, Kato T, Pryor-Koishi K, Nakanishi I, Fujita T, Imayoshi Y, Markoff A, Yanagihara I, Udagawa Y, Kurahashi H.
  • Organizer: 59th Annual Clinical Meeting, ACOG
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20110430-0504
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans. Keystone Symposia: Functional Consequences of Structural Variation in the Genome (2011)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H.
  • Organizer: Steamboat Springs
  • Place of Presentation: Colorado, USA
  • Year and Date: 20110108-13
• [Remarks] 藤田保健衛生大学・総合医科学研究所
  • URL: http://www.fujita-hu.ac.jp/ICMS/
• [Remarks] 分子遺伝学研究部門
  • URL: http://www.fujita-hu.ac.jp/?genome/mg/
• [Remarks] 研究代表者が運営
  • URL: http://www.fujita-hu.ac.jp/?genome/11&22/