子宮－胚間の協調的なエピゲノム調節と胚の活性化

• Project Area: Analyses and regulation of germline epigenome
• Project/Area Number: 26112506
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 廣田 泰 東京大学, 医学部附属病院, 講師 (40598653)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 子宮内膜 / 胚盤胞 / エピゲノム / 胚の活性化 / エストロゲン / DNAメチル化 / 低酸素誘導因子 / ホメオボックス遺伝子 / 子宮 / 胚 / プロゲステロン / 子宮頸部 / microRNA

Outline of Annual Research Achievements

受精卵は着床直前に子宮内に移入し、子宮の作用によって活性化され、子宮への接着反応を開始する。着床により胚の細胞分化が加速し、胚のDNAメチル化は着床の前後でダイナミックに促進されるが、そのタイミングの詳細は明らかでない。初期胚発生の後半（着床直前）の過程で、子宮‐胚間の協調的な作用が必須と考えられているが、その分子機構は不明である。初期胚の発生は子宮からの刺激がなければ胚盤胞の状態で休眠状態となって止まるが、卵巣からのエストロゲンの刺激を子宮が受けると、子宮内膜からの何らかの生理活性物質の分泌によって胚は活性化され胚の接着反応が開始するという、胚盤胞活性化の機構が存在すると考えられている。本年度の研究では、エストロゲンの有無で着床制御が可能である着床遅延マウスモデルの実験系を用いて、着床前の活性化胚盤胞と休眠胚盤胞を回収してRNA-seqおよびMeDIP-seqを行った。活性化胚でtranscriptionが促進され、DNAの脱メチル化を受けている遺伝子は約1400個を抽出した。着床直前の子宮において胚のエピジェネティックな遺伝子調節が起こっていることが示唆された。エストロゲンの作用は子宮内膜由来の物質を介して作用していることから、特定の経路同定を進めている。また、子宮特異的HIF2α欠損マウスを用いた検討から、子宮の低酸素誘導因子HIF2αが着床位置調節等により着床を調節していること、ホメオボックス遺伝子MSXの子宮特異的欠損マウスの解析から、MSXが子宮上皮の細胞極性保持と子宮間質のNFkB抑制により着床を調節していることが明らかになった。本研究から、子宮内環境による着床期胚の活性化のエピゲノム調節と着床の分子機構の詳細が明らかになった。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] シンシナティ小児病院(米国)
• [Journal Article] STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation. (2016)
  • Author(s): Hiraoka T, Hirota Y, Saito-Fujita T, Matsuo M, Egashira M, Matsumoto L, Haraguchi H, Dey SK, Furukawa KS, Fujii T, Osuga Y.
  • Journal Title: JCI Insight Volume: 1 Issue: 8
  • DOI: 10.1172/jci.insight.87591
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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: 101 Issue: 6 Pages: 2371-2379
  • DOI: 10.1210/jc.2016-1515
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: 428 Pages: 161-169
  • DOI: 10.1016/j.mce.2016.03.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: American Journal of Reproductive Immunology Volume: 75 Issue: 4 Pages: 486-492
  • DOI: 10.1111/aji.12489
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: American Journal of Reproductive Immunology Volume: 74 Issue: 6 Pages: 480-486
  • DOI: 10.1111/aji.12426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Gynecological Endocrinology Volume: 31 Issue: 10 Pages: 783-787
  • DOI: 10.3109/09513590.2015.1062862
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells. (2015)
  • Author(s): Miyashita, M., Koga, K., Izumi, G., Makabe, T., Hasegawa, A., Hirota, Y., Hirata, T., Harada, M., Fujii, T., Osuga, Y
  • Journal Title: Fertility and Sterility Volume: 104 Issue: 1 Pages: 217-24
  • DOI: 10.1016/j.fertnstert.2015.03.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus. (2015)
  • Author(s): Cha, J., Burnum-Johnson, K.E., Bartos, A., Li, Y., Baker, ES., Tilton, S.C., Webb-Robertson, B.J., Piehowski, P.D., Monroe, M.E., Jegga, A.G., Murata, S., Hirota, Y., Dey, S.K.
  • Journal Title: The Journal of Biological Chemistry Volume: 290 Issue: 24 Pages: 15337-15349
  • DOI: 10.1074/jbc.m115.655001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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, Takamura M, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: epub Issue: 6 Pages: 501-506
  • DOI: 10.1111/aji.12359
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Issue: 3 Pages: 87-94
  • DOI: 10.1274/jmor.32.87
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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
• [Journal Article] 藤田知子, 廣田泰. (2015)
  • Author(s): 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
  • 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
• [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] MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation. (2014)
  • Author(s): Hirofumi Haraguchi, Tomoko Saito-Fujita, Yasushi Hirota, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Naoko Yamauchi, Masashi Fukayama, Amanda Bartos, Jeeyeon Cha, Sudhansu K. Dey, Tomoyuki Fujii, Yutaka Osuga.
  • Journal Title: Mol Endocrinol. Volume: 28(7) Issue: 7 Pages: 1108-17
  • DOI: 10.1210/me.2014-1097
  • Peer Reviewed
• [Journal Article] Application of detergents or high hydrostatic pressure as decellularization process in uterine tissues and their subsequent effects on in vivo uterine regeneration in murine models (2014)
  • Author(s): E.G.Santoso, K.Yoshida, Y.Hirota, M.Aizawa,O.Yoshino, A.Kishida, Y.Osuga, S.Saito, T.Ushida, K.S.Furukawa,
  • Journal Title: PLoS ONE Volume: 9 Issue: 7 Pages: 1-13
  • DOI: 10.1371/journal.pone.0103201
  • Peer Reviewed / Open Access
• [Journal Article] IL-1β increases expression of tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells. (2014)
  • Author(s): Urata Y, Koga K, Hirota Y, Akiyama I, Izumi G, Takamura M, Nagai M, Harada M, Hirata T, Yoshino O, Kawana K, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol. Volume: 72 Issue: 5 Pages: 496-503
  • DOI: 10.1111/aji.12282
  • Peer Reviewed / Open Access
• [Journal Article] Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis. (2014)
  • Author(s): Miyashita M, Koga K, Takamura M, Izumi G, Nagai M, Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y.
  • Journal Title: Gynecol Endocrinol. Volume: 30 Issue: 9 Pages: 644-648
  • DOI: 10.3109/09513590.2014.911279
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Bone Morphogenetic Protein 6 in Accumulation and Regulation of Neutrophils in the Human Ovary. (2014)
  • Author(s): Akiyama I, Yoshino O, Osuga Y, Shi J, Takamura M, Harada M, Koga K, Hirota Y, Hirata T, Fujii T, Saito S, Kozuma S.
  • Journal Title: Reproductive Sciences Volume: 21 Issue: 6 Pages: 772-777
  • DOI: 10.1177/1933719113518988
  • Peer Reviewed
• [Journal Article] Bone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cells. (2014)
  • Author(s): Akiyama I, Yoshino O et al.
  • Journal Title: Reprod Sci. Volume: 21(4) Issue: 4 Pages: 477-82
  • DOI: 10.1177/1933719113503411
  • Peer Reviewed
• [Journal Article] 着床における黄体ホルモン(プロゲステロン)の作用. (2014)
  • Author(s): 藤田知子，廣田泰
  • Journal Title: 医学のあゆみ Volume: 248 Pages: 914-915
• [Journal Article] 着床期子宮におけるプロゲステロンの作用機構 (2014)
  • Author(s): 廣田泰，藤田知子，大須賀穣，藤井知行
  • Journal Title: 日本生殖免疫学会誌 Volume: 29 Pages: 6-11
  • NAID: 130005111147
• [Presentation] MicroRNA-200a impairs progesterone signaling in the cervix, disturbing embryo implantation. (2016)
  • Author(s): Hirota Y, Haraguchi H,Saito-Fujita T, Egashira M, Matsumoto L, Matsuo M, Hiraoka T, Koga K, Dey SK, Osuga Y, Fujii T.
  • 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): Hiraoka T, Hirota Y.
  • 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): Hiraoka T, Hirota Y.
  • Organizer: 平成２７年度「がん研究分野の特性等を踏まえた支援活動」冬期シンポジウム
  • Place of Presentation: 一橋講堂 学術総合センター（東京都千代田区）
  • Year and Date: 2016-02-07
• [Presentation] プロゲステロンと子宮の機能～着床から分娩まで (2016)
  • Author(s): 廣田泰
  • Organizer: 第5回プロゲスチン研究会
  • Place of Presentation: ホテル椿山荘東京（東京都文京区）
  • Year and Date: 2016-02-06
  • Invited
• [Presentation] Endometrial regeneration in the mouse model of decellularized matrix transplantation. (2015)
  • Author(s): Hiraoka T, Hirota Y, Saito-Fujita T, Tanaka T, Matsuo M, Egashira M, Matsumoto L, Haraguchi H, Furukawa KS, Osuga Y, Fujii T.
  • Organizer: 第38回日本分子生物学会年会 (BMB 2015)
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-02
• [Presentation] 子宮の低酸素誘導因子HIF2αは妊娠成立に必須である (2015)
  • Author(s): 松本玲央奈、廣田泰、藤田知子、原口広史、江頭真宏、松尾光徳、平岡毅大、田中智基、武田憲彦、大須賀穣、藤井知行
  • Organizer: 第33回日本受精着床学会総会・学術講演会
  • Place of Presentation: TFTホール（東京都江東区）
  • Year and Date: 2015-11-27
• [Presentation] 着床における低酸素誘導因子HIFの意義 (2015)
  • Author(s): 松本玲央奈、廣田泰、藤田知子、原口広史、江頭真宏、松尾光徳、平岡毅大、田中智基、武田憲彦、大須賀穣、藤井知行
  • Organizer: 第30回日本生殖免疫学会
  • Place of Presentation: くまもと県民交流館パレア（熊本県熊本市）
  • Year and Date: 2015-11-21
• [Presentation] 黄体ホルモンが調節する子宮内膜の胚受容能 (2015)
  • Author(s): 廣田泰
  • Organizer: 第6回金沢大学学際科学実験センターシンポジウム
  • Place of Presentation: 金沢大学附属医学図書館（石川県金沢市）
  • Year and Date: 2015-11-13
  • Invited
• [Presentation] The presence of ovarian hormone-independent endometrial epithelial growth in endometrial remodeling and regeneration. (2015)
  • Author(s): Takehiro Hiraoka, Yasushi Hirota
  • Organizer: The Second International Meeting for Epithelial Tubulology
  • Place of Presentation: 北海道大学医学部学友会館（北海道札幌市）
  • Year and Date: 2015-08-22
  • Int'l Joint Research / Invited
• [Presentation] Crucial role of hypoxia inducible factor 2α in the pregnant uterus. (2015)
  • Author(s): Matsumoto L, Hirota Y, Saito-Fujita T, Haraguchi H, Egashira M, Matsuo M, Hiraoka T, Koga K, Dey SK, Fujii T, Osuga Y.
  • Organizer: 31st ESHRE Annual Meeting (ESHRE 2015)
  • Place of Presentation: FIL International Lisbon Fair （Portugal, Lisbon）
  • Year and Date: 2015-06-15
  • Int'l Joint Research
• [Presentation] 黄体ホルモンによる妊娠成立・維持のしくみ (2015)
  • Author(s): 廣田泰
  • Organizer: 第38回東京成長ホルモン成長因子セミナー
  • Place of Presentation: 新宿住友ホール（東京都新宿区）
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] 子宮におけるプロゲステロン受容体シグナルと着床 (2015)
  • Author(s): 廣田泰
  • Organizer: 第60回日本生殖医学会学術講演会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-27
  • Invited
• [Presentation] The presence of cellular senescence and its possible roles in the postpartum uterus. (2015)
  • Author(s): Egashira M, Hirota Y, Saito-Fujita T, Haraguchi H, Matsumoto L, Matsuo M, Hiraoka T, Osuga Y, Fujii T.
  • 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): Haraguchi H, Hirota Y, Saito-Fujita T, Egashira M, Matsumoto L, Matsuo M, Hiraoka T, Koga K, Dey SK, Osuga Y, Fujii T.
  • 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] 黄体ホルモンによる子宮内膜の機能調節と着床 (2014)
  • Author(s): 廣田泰
  • Organizer: 第29回日本生殖免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2014-12-12
  • Invited
• [Presentation] プロゲステロンによる子宮内膜の機能調節と着床 (2014)
  • Author(s): 廣田泰
  • Organizer: 第59回日本生殖医学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] Decidual cellular senescence contributes to preterm delivery. (2014)
  • Author(s): 廣田泰
  • Organizer: 46th International Congress on Pathophysiology of Pregnancy / 35th Japan Society for the Study of Hypertension in Pregnancy.
  • Place of Presentation: 東京
  • Year and Date: 2014-09-19
  • Invited
• [Presentation] MicroRNA-200a confers progesterone signaling deficiency making the cervix unfavorable to embryo implantation (2014)
  • Author(s): Hirota Y
  • Organizer: Gordon Research Conference on Mammalian Reproduction
  • Place of Presentation: New London, USA
  • Year and Date: 2014-08-13
  • Invited
• [Presentation] 妊娠成立に関わるプロゲステロン・シグナルの意義とその調節機構 (2014)
  • Author(s): 廣田泰
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24
  • Invited
• [Book] Uterine Endometrial Function. (2016)
  • Author(s): Yasushi Hirota
  • Total Pages: 155
  • Publisher: Springer
• [Remarks] Researchmap：廣田泰
  • URL: http://researchmap.jp/yhirota-tky/