早産におけるプロゲステロンの標的遺伝子の同定と機能解析

2015 Fiscal Year Annual Research Report

• Project/Area Number: 15K15597
• Research Institution: The University of Tokyo
• Principal Investigator: 金谷 真由子 東京大学, 医学部附属病院, 助教 (60748862)
• Co-Investigator(Kenkyū-buntansha): 廣田 泰 東京大学, 医学部附属病院, 講師 (40598653)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Keywords: 早産 / プロゲステロン / 黄体ホルモン / RNA-seq / プロゲステロン受容体 / ChIP-seq / 脱落膜 / 子宮

Outline of Annual Research Achievements

黄体ホルモン（プロゲステロン、P）はその受容体（PR）を介して働き、子宮にはPRが強く発現していることが知られている。陣痛時に血中P濃度は変化せず、子宮のPR応答性低下が起こっている。早期に陣痛発来する自然早産では、「子宮のPR応答性の早期減弱」が病因に関与している可能性がある。早産子宮ではPRの標的遺伝子が正期産子宮と比べ低下していると推測される。早産・正期産の胎盤（卵膜）に付着した脱落膜から分離培養したヒト子宮内膜細胞を用いて、P添加によるmRNA発現の変化をRNA-seqで、PRの転写ターゲットを免疫沈降シーケンシング（ChIP-seq）で解析し、早産におけるPRの標的遺伝子を見出したいと考えて研究を行った。正期産と早産の経腟分娩胎盤の卵膜から子宮脱落膜細胞を分離培養し、P添加で増加するtranscriptをRNA-seqで抽出し、一方でPRの転写調節のターゲットを免疫沈降シーケンシングで抽出した。これらのデータを合わせて、早産検体で低下しているP応答遺伝子群を抽出した。現在、これらのP応答遺伝子のうち、早産に関わる機能を有するものを抽出するため、個別の遺伝子の機能解析を行っている。本研究により、早産の機序としてのP応答性低下とそのメカニズムの解明の糸口を見出した。

Research Products

• [Int'l Joint Research] シンシナティ小児病院(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: シンシナティ小児病院
• [Journal Article] Effects of 1,25-dihydroxy vitamin D3 on endometriosis. (2016)
  • Author(s): Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A, Nagai M, Urata Y, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Clin Endocrinol Metab Volume: in press Pages: in press
  • DOI: jc20161515
  • Peer Reviewed
• [Journal Article] A potential role of endoplasmic reticulum stress in development of ovarian hyperstimulation syndrome. (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Yoshino O, Urata Y, Izumi G, Takamura M, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Mol Cell Endocrinol Volume: in press Pages: in press
  • DOI: 10.1016/j.mce.2016.03.032.
  • Peer Reviewed
• [Journal Article] Resveratrol Enhances Apoptosis in Endometriotic Stromal Cells. (2016)
  • Author(s): Taguchi A, Koga K, Kawana K, Makabe T, Sue F, Miyashita M, Yoshida M, Urata Y, Izumi G, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: 75 Pages: 486-492
  • DOI: 10.1111/aji.12489.
  • Peer Reviewed
• [Journal Article] Identification of TRIM22 as a progesterone-responsive gene in Ishikawa endometrial cancer cells. (2015)
  • Author(s): Saito-Kanatani M, Urano T, Hiroi H, Momoeda M, Ito M, Fujii T, Inoue S.
  • Journal Title: J Steroid Biochem Mol Biol Volume: 154 Pages: 217-225
  • DOI: 10.1016/j.jsbmb.2015.08.024.
  • Peer Reviewed
• [Journal Article] Simultaneous Detection and Evaluation of Four Subsets of CD4+ T Lymphocyte in Lesions and Peripheral Blood in Endometriosis. (2015)
  • Author(s): Takamura M, Koga K, Izumi G, Hirata T, Harada M, Hirota Y, Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol. Volume: 74 Pages: 480-486
  • DOI: 10.1111/aji.12426.
  • Peer Reviewed
• [Journal Article] Evidence of the activation of unfolded protein response in granulosa and cumulus cells during follicular growth and maturation. (2015)
  • Author(s): Harada M, Nose E, Takahashi N, Hirota Y, Hirata T, Yoshino O, Koga K, Fujii T, Osuga Y.
  • Journal Title: Gynecol Endocrinol. Volume: 31 Pages: 783-787
  • DOI: 10.3109/09513590.2015.1062862.
  • Peer Reviewed
• [Journal Article] Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus. (2015)
  • Author(s): Cha J, Burnum-Johnson KE, Bartos A, Li Y, Baker ES, Tilton SC, Webb-Robertson BJ, Piehowski PD, Monroe ME, Jegga AG, Murata S, Hirota Y, Dey SK.
  • Journal Title: J Biol Chem Volume: 290 Pages: 15337-15349
  • DOI: 10.1074/jbc.M115.655001.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] プロテオミクスを用いた妊娠成立・維持機構の研究. (2015)
  • Author(s): 松尾光徳, 廣田泰.
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 22 Pages: 11-17
• [Journal Article] Cyclic stretch augments production of neutrophil chemokines, matrix metalloproteinases, and activin A in human endometrial stromal cells. (2015)
  • Author(s): Izumi G, Koga K, Nagai M, Urata Y, Takamura M, Harada M, Hirata T, Hirota Y, Ogawa K, Inoue S, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: 73 Pages: 501-506
  • DOI: 10.1111/aji.12359.
  • Peer Reviewed
• [Journal Article] How does Progesterone Support Embryo Implantation? (2015)
  • Author(s): Hiraoka T, Saito-Fujita T, Hirota Y.
  • Journal Title: J Mamm Ova Res Volume: 32 Pages: 87-94
  • DOI: 10.1274/jmor.32.87
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 急速に増大した仙尾部未熟奇形腫のため妊娠22週で子宮内胎児死亡となった1例 (2015)
  • Author(s): 矢野倫子、田口歩、齋藤真由子、中澤直子
  • Journal Title: 東京産科婦人科学会会誌 Volume: 64 Pages: 30-33
• [Journal Article] 着床における黄体ホルモンの作用 (2015)
  • Author(s): 平岡毅大、廣田泰
  • Journal Title: 産科と婦人科 Volume: 82 Pages: 740-745
• [Journal Article] 子宮内膜における着床制御因子 プロゲステロン・シグナルを中心に (2015)
  • Author(s): 藤田知子、廣田泰
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 22 Pages: 176-179
• [Journal Article] 種差からみた着床 ヒトとの共通点と相違点 (2015)
  • Author(s): 江頭真宏、廣田泰
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 22 Pages: 183-189
• [Presentation] MicroRNA-200a impairs progesterone signaling in the cervix, disturbing embryo implantation. (2016)
  • Author(s): Yasushi Hirota, Hirofumi Haraguchi, Tomoko Saito-Fujita, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Sudhansu K. Dey, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: International Symposium on Epigenome Dynamics and Regulation in Germ Cells
  • Place of Presentation: 京都大学百周年時計台記念館（京都府京都市）
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [Presentation] Endometrial regeneration in the mouse model of decellularized matrix transplantation. (2016)
  • Author(s): Takehiro Hiraoka, Yasushi Hirota.
  • Organizer: International Symposium on Epigenome Dynamics and Regulation in Germ Cells
  • Place of Presentation: 京都大学百周年時計台記念館（京都府京都市）
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [Presentation] Endometrial regeneration in the mouse model of decellularized matrix transplantation. (2015)
  • Author(s): Takehiro Hiraoka, Yasushi Hirota, Tomoko Saito-Fujita, Tomoki Tanaka, Mitsunori Matsuo, Mahiro Egashira, Leona Matsumoto, Hirofumi Haraguchi, Katsuko S. Furukawa, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: 第38回日本分子生物学会年会 (BMB 2015)
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-02
• [Presentation] Crucial role of hypoxia inducible factor 2α in the pregnant uterus. (2015)
  • Author(s): Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Mahiro Egashira, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Sudhansu K. Dey, Tomoyuki Fujii, Yutaka Osuga.
  • Organizer: 31st ESHRE Annual Meeting (ESHRE 2015)
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2015-06-15
  • Int'l Joint Research
• [Presentation] The presence of cellular senescence and its possible roles in the postpartum uterus. (2015)
  • Author(s): Mahiro Egashira, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: IFFS/JSRM International Meeting 2015
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-26
  • Int'l Joint Research
• [Presentation] MicroRNA controls receptivity to the embryo by regulating progesterone signaling in the cervix and uterus. (2015)
  • Author(s): Hirofumi Haraguchi, Yasushi Hirota, Tomoko Saito-Fujita, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Sudhansu K. Dey, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: IFFS/JSRM International Meeting 2015
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-26
  • Int'l Joint Research
• [Book] Uterine Endometrial Function (2016)
  • Author(s): Yasushi Hirota
  • Total Pages: in press
  • Publisher: Springer