Transcriptional regulation via DNA secondary structure: novel epigenetic mechanism

• Project/Area Number: 26670171
• 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): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: グアニン四重鎖 / DNA二次構造 / プロモーター / アネキシン / 多型 / 習慣流産 / エピゲノム / アネキシンV / ２次構造 / バイサルファイト法 / 2次構造

Outline of Final Research Achievements

The polymorphisms in the ANXA5 promoter region are associated with recurrent pregnancy loss. The female carriers of M2 haplotype are at high risk of the pregnancy loss. The placenta from the M2 carrier has low level of ANXA5 transcript since the promoter activity of the M2 is low. We identified the consensus sequence for Guanine-quadraplex (G4) formation at this promoter region. We analyzed the potential secondary structure by bisulfite treatment followed by next generation sequencing. The pattern of C-to-T conversion indicated that the polymorphism affected the potential for G4. These data suggest that the low expression levels of ANXA5 via G4 formation induce hypercoagulation leading to high risk of pregnancy loss in M2 carriers.

Research Products

• [Int'l Joint Research] ミュンスター大学(ドイツ)
• [Journal Article] TUBA1A mutation can cause a hydranencephaly-likesevere form of cortical dysgenesis. (2015)
  • Author(s): Yokoi S, Ishihara N, Miya F, Tsutsumi M, Yanagihara I, Fujita N, Yamamoto H, Kato M, Okamoto N, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Kojima S, Saitoh S, Kurahashi H, Natsume J.
  • Journal Title: Sci Rep. Volume: 23 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep15165
  • Peer Reviewed / Open Access
• [Journal Article] Whole Genomic Analysis of an Unusual Human G6P[14] Rotavirus Strain Isolated from a Child with Diarrhea in Thailand: Evidence for Bovine-To-Human Interspecies Transmission and Reassortment Events (2015)
  • Author(s): Tacharoenmuang R, Komoto S, Guntapong R, Ide T, Haga K, Katayama K, Kato T, Ouchi Y, Kurahashi H, Tsuji T, Sangkitporn S, Taniguchi K.
  • Journal Title: PLoS One Volume: 10(9) Issue: 9 Pages: 1-23
  • DOI: 10.1371/journal.pone.0139381
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Emergence and Characterization of Unusual DS-1-Like G1P[8] Rotavirus Strains in Children with Diarrhea in Thailand (2015)
  • Author(s): Komoto S, Tacharoenmuang R, Guntapong R, Ide T, Haga K, Katayama K, Kato T, Ouchi Y, Kurahashi H, Tsuji T, Sangkitporn S, Taniguchi K.
  • Journal Title: PLoS One Volume: 10(11) Issue: 11 Pages: 1-22
  • DOI: 10.1371/journal.pone.0141739
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A unique TBX5 microdeletion with microinsertion detected in patient with Holt-Oram syndrome. (2015)
  • Author(s): Morine M, et al.
  • Journal Title: Am J Med Genet A Volume: 167 Issue: 12 Pages: 3192-3196
  • DOI: 10.1002/ajmg.a.37359
  • Peer Reviewed
• [Journal Article] Intragenic duplication in the PKHD1 gene in autosomal recessive polycystic kidney disease. (2015)
  • Author(s): Miyazaki J, et al.
  • Journal Title: BMC Med Genet Volume: 16 Issue: 1 Pages: 98-98
  • DOI: 10.1186/s12881-015-0245-3
  • Peer Reviewed / Open Access
• [Journal Article] Preimplantation genetic diagnosis/screening by comprehensive molecular testing (2015)
  • Author(s): Kurahashi H, Kato T, Miyazaki J, Nishizawa H, Nishio E, Furukawa H, Miyamura H, Ito M, Endo T, Ouchi Y, Inagaki H, Fujii T
  • Journal Title: Reprod Med Biol Volume: 15 Issue: 1 Pages: 13-19
  • DOI: 10.1007/s12522-015-0216-6
  • Peer Reviewed
• [Journal Article] Nine-year follow-up in a child with chromosomal integration of human herpesvirus 6 transmitted from an unrelated donor through the Japan Marrow Donor Program (2015)
  • Author(s): Yagasaki H, Shichino H, Shimizu N, Ohye T, Kurahashi H, Yoshikawa T, Takahashi S
  • Journal Title: Transpl Infect Dis Volume: 17 Issue: 1 Pages: 160-161
  • DOI: 10.1111/tid.12338
  • Peer Reviewed
• [Journal Article] PCSK5 mutation in a patient with the VACTERL association (2015)
  • Author(s): Nakamura Y. et al.
  • Journal Title: BMC Res Notes Volume: 8 Issue: 1 Pages: 228-228
  • DOI: 10.1186/s13104-015-1166-0
  • Peer Reviewed / Open Access
• [Journal Article] Novel FATP4 mutations responsible for ichthyosis prematurity syndrome in a Japanese patient (2015)
  • Author(s): Tsuge I, Morishita M, Kato T, Tsutsumi M, Inagaki H, Mori Y, Yamawaki K, Inuo C, Ieda K, Ohye T, Hayakawa A, Kurahashi H
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15003-15003
  • DOI: 10.1038/hgv.2015.3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Age-related decrease of meiotic cohesins in human oocyte (2014)
  • Author(s): Tsutsumi M, Fujiwara R, Nishizawa H, Ito M, Kogo H, Inagaki H, Ohye T, Kato T, Fujii T, Kurahashi H
  • Journal Title: PLoS One Volume: 9, Issue: 5 Pages: 1-8
  • DOI: 10.1371/journal.pone.0096710
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dual roles for the telomeric repeats in chromosomally integrated human herpesvirus-6. (2014)
  • Author(s): Ohye T, Inagaki H, Ihira M, Higashimoto Y, Kato K, Oikawa J, Yagasaki H, Niizuma T, Takahashi Y, Kojima S, Yoshikawa T, Kurahashi H
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 4559-4559
  • DOI: 10.1038/srep04559
  • Peer Reviewed / Open Access
• [Journal Article] Breakpoint analysis of the recurrent constitutional t(8;22)(q24.13;q11.21) translocation (2014)
  • Author(s): Mishra D, Kato T, Inagaki H, Kosho T, Wakui K, Kido Y, Sakazume S, Taniguchi-Ikeda M, Morisada N, Iijima K, Fukushima Y, Emanuel BS, Kurahashi H
  • Journal Title: Mol Cytogenet Volume: 7 Issue: 1 Pages: 55-55
  • DOI: 10.1186/s13039-014-0055-x
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Signature of backward replication slippage at the copy number variation junction. (2014)
  • Author(s): Ohye T, Inagaki H, Ozaki M, Ikeda T, Kurahashi H
  • Journal Title: J Hum Genet Volume: in press Issue: 5 Pages: 247-250
  • DOI: 10.1038/jhg.2014.20
  • Peer Reviewed
• [Journal Article] Analysis of the t(3;8) of hereditary renal cell carcinoma: A palindrome mediated translocation (2014)
  • Author(s): Kato T, Franconi CP, Sheridan MB, Hacker AM, Inagakai H, Glover TW, Arlt MF, Drabkin HA, Gemmill RM, Kurahashi H, Emanuel BS
  • Journal Title: Cancer Genet Volume: 207 Issue: 4 Pages: 133-140
  • DOI: 10.1016/j.cancergen.2014.03.004
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of Emanuel syndrome: theoretical frequency and surveillance result (2014)
  • Author(s): Ohye T, Inagaki H, Kato T, Tsutsumi M, Kurahashi H
  • Journal Title: Pediatr Int Volume: 56 Issue: 4 Pages: 462-466
  • DOI: 10.1111/ped.12437
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency (2014)
  • Author(s): Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, Kurahashi H, Yoshikawa T, Katano H, Inoue N, Imai K, Takagi M, Morio T, Mizutani S
  • Journal Title: Clin Infect Dis Volume: 59 Issue: 4 Pages: 545-548
  • DOI: 10.1093/cid/ciu323
  • Peer Reviewed / Open Access
• [Journal Article] An immunocompetent child with chromosomally integrated human herpesvirus 6B accidentally identified during the care of Mycoplasma pneumoniae infection (2014)
  • Author(s): Oikawa J, Tanaka J, Yoshikawa T, Morita Y, Hishiki H, Ishiwada N, Ohye T, Kurahashi H, Kohno Y
  • Journal Title: J Infect Chemother Volume: 20 Issue: 1 Pages: 65
  • DOI: 10.1016/j.jiac.2013.07.004
  • Peer Reviewed
• [Journal Article] Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient. (2014)
  • Author(s): Tsuge I, Ito K, Ohye T, Kando N, Kondo Y, Nakajima Y, Inuo C, Kurahashi H, Urisu A
  • Journal Title: Pediatr Pulmonol Volume: 49 Issue: 3
  • DOI: 10.1002/ppul.22814
  • Peer Reviewed
• [Journal Article] Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case (2014)
  • Author(s): Hibi Y, Ohye T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, Mizuno Y, Uchino S, Kosugi S, Kurahashi H, Iwase K
  • Journal Title: Surg Today Volume: 44 Issue: 11 Pages: 2195-2200
  • DOI: 10.1007/s00595-013-0826-8
  • Peer Reviewed
• [Journal Article] A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis (2014)
  • Author(s): Hibi Y, Ohye T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, Mizuno Y, Kurahashi H, Iwase K
  • Journal Title: Endocr J Volume: 61 Pages: 19-23
  • NAID: 130004443932
  • Peer Reviewed
• [Journal Article] Serum liver-type fatty acid-binding protein predicts recovery of graft function after kidney transplantation from donors after cardiac death (2014)
  • Author(s): Kawai A, Kusaka M, Kitagawa F, Ishii J, Fukami N, Maruyama T, Sasaki H, Shiroki R, Kurahashi H, Hoshinaga K
  • Journal Title: Clin Transplant Volume: 28 Issue: 6 Pages: 749-754
  • DOI: 10.1111/ctr.12375
  • Peer Reviewed / Open Access
• [Presentation] Massive parallel sequencing revealed the conformational dynamics of the non-B form DNA at the promoter (2015)
  • Author(s): Inagaki H, Miyamura H, Tsutsumi M, Kato T, Nishizawa H, Kurahashi H
  • Organizer: ASHG2015
  • Place of Presentation: Baltimore
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] Breakpoint analysis of the recurrent constitutional t(8;22) (q24.13;q11.21) translocation (2015)
  • Author(s): Kurahashi H, Mishra D, Kato T, Inagaki H, Kosho T, Wakui K et al.
  • Organizer: ESHG2015
  • Place of Presentation: Glasgow
  • Year and Date: 2015-06-06
  • Int'l Joint Research
• [Presentation] Deep sequencing of sodium bisulfite-treated genomic DNA revealed in vivo G-quadruplex structure affecting the gene expression of ANXA5 that causes obstetric complications. (2015)
  • Author(s): Inagaki H, Ota S, Nishizawa H, Miyamura H, Nakahira M, Suzuki M et al.
  • Organizer: The 11th International Workshop on Advanced Genomics
  • Place of Presentation: Tokyo
  • Year and Date: 2015-05-20
  • Int'l Joint Research
• [Presentation] Breakpoint analysis of the recurrent constitutional t(8;22)(q24;q11) translocation (2015)
  • Author(s): Kato T, Inagaki H, Mishura D, Ouchi Y, Tsutsumi M, Ohye T et al.
  • Organizer: The 11th International Workshop on Advanced Genomics
  • Place of Presentation: Tokyo
  • Year and Date: 2015-05-20
  • Int'l Joint Research
• [Presentation] Age-related increase of aneuploidy in human oocytes (2015)
  • Author(s): Kurahashi H
  • Organizer: IFFS/JSRM International Meeting 2015
  • Place of Presentation: Yokohama
  • Year and Date: 2015-04-26
  • Int'l Joint Research / Invited
• [Presentation] Detection of in vivo G-quadruplex structure of the ANXA5 promoter that contributes to the recurrent pregnancy loss (2014)
  • Author(s): Inagaki H, Ota S, Miyamura H, Tsutsumi M, Kato T, Nishizawa H, Yanagihara I, Kurahashi H
  • Organizer: ASHG 2014
  • Place of Presentation: San Diego, CA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] Two cases of lissencephaly with marked hydrocephalus caused by TUBA1A mutation (2014)
  • Author(s): Ishihara N, Yokoi S, Yamamoto H, Natsume J, Tsutsumi M, Ohye T, Kato M, Saito S, Kurahashi H. Two cases of lissencephaly with marked hydrocephalus caused by TUBA1A mutation
  • Organizer: ASHG 2014
  • Place of Presentation: San Diego, CA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] EFNB1 mutation found in patients with craniofrontonasal syndrome in a Japanese family (2014)
  • Author(s): Kato H, Okumoto T, Yoshimura Y, Taguchi Y, Sugimoto M, Inagaki H, Kurahashi H
  • Organizer: The 10th Asian Pacific Craniofacial Association Conference
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2014-10-03 – 2014-10-05
• [Presentation] Cytogenetic analysis of monopronucleated (1PN) zygotes after intracytoplasmic sperm injection and conventional in-vitro fertilization (2014)
  • Author(s): Nishiyama S, Kato T, Kani C, Miyazaki J, Nishizawa H, Ochi M, Fujii T, Kurahashi H
  • Organizer: International Society for Mild Approaches in Assisted Reproduction
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2014-09-10 – 2014-09-12
• [Presentation] Obstetric complication-associated ANXA5 promoter polymorphisms affect gene expression via G-quadruplex structure in vivo (2014)
  • Author(s): Inagaki H, Ota S, Nishizawa H, Miyamura H, Nakahira K, Suzuki M, Tsutsumi M, Kato T, Nishiyama S, Udagawa Y, Yanagihara I, Kurahashi H
  • Organizer: FASEB SRC, Dynamic DNA Structures in Biology
  • Place of Presentation: Itasca, Illinois
  • Year and Date: 2014-07-20 – 2014-07-25
• [Presentation] Age-related decrease of meiotic cohesins in human oocytes (2014)
  • Author(s): Kurahashi H, Tsutsumi M, Fujiwara R, Nishizawa H, Kogo H, Inagaki H, Ohye T, Kato T, Fujii T
  • Organizer: Eshre 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-06-29 – 2014-07-02
• [Book] Clinical Genomics: Practical Applications in Adult Patient Care (2014)
  • Author(s): Nisizawa H, Kurahashi H
  • Total Pages: 928
  • Publisher: McGraw-Hill Professional
• [Remarks] 藤田保健衛生大学・総合医科学研究所・分子遺伝学研究部門
  • URL: http://www.fujita-hu.ac.jp/~genome/mg/
• [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] 藤田保健衛生大学・疾患遺伝子網羅的解析センター
  • URL: http://www.fujita-hu.ac.jp/~gtac/
• [Remarks] t(11;22)
  • URL: http://www.fujita-hu.ac.jp/~genome/11&22/