Regulation of Erythropoietin production and its roles on adult hematopoiesis

• Project/Area Number: 24591404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: MINEGISHI Naoko 東北大学, 東北メディカル・メガバンク機構, 教授 (40271895)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Mikiko 東北大学, 医学系研究科, 講師 (80508309)
• Research Collaborator: HIRANO Ikuo 東北大学, 大学院医学系研究科, 助教 (00708117) ; SUZUKI Norio 東北大学, 大学院医学系研究科, 講師 (20447254) ; SOUMA Tomokazu ; YAMAZAKI Shun
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 遺伝子発現制御 / エリスロポエチン / 赤血球造血 / 腎性貧血 / 転写因子 / 低酸素応答性 / 血液内科学 / 赤血球 / 転写調節 / 神経堤細胞

Outline of Final Research Achievements

Erythropoietin, secreted from adult kidney, is essential for erythropoiesis. We made ISAM (Inherited Super Anemic Mice), which exhibited Epo-deficient-anemia in their adulthood. We found the significantly decreased number of proerythroblasts and basophilic erythroblasts in their bone marrow, and several downstream-genes of Epo signals in bone marrow cells. Epo producing cells of ISAM were demonstrated as the cells expressing green fluorescence, among cortical fibroblasts in adult kidneys, and also in the portion of embryonic neural cells and neural crest cells. In the experimental fibrotic kidneys, Epo-producing cells transformed into myofibroblasts and halted Epo production. These changes were reversible. We have an impression that the inhibition of inflammatory signals might be a novel therapeutic strategy for renal fibrosis and renal anemia.

Research Products

• [Journal Article] Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection. (2016)
  • Author(s): Otsuki A, Suzuki M, Katsuoka F, Tsuchida K, Suda H, Morita M, Shimizu R, Yamamoto M.
  • Journal Title: Free Radic Biol Med Volume: 91 Pages: 45-57
  • DOI: 10.1016/j.freeradbiomed.2015.12.005
  • Peer Reviewed
• [Journal Article] Adjustment of Cell-Type Composition Minimizes Systematic Bias in Blood DNA Methylation Profiles Derived by DNA Collection Protocols. (2015)
  • Author(s): Shiwa Y, Hachiya T, Furukawa R, Ohmomo H, Ono K, Kudo H, Hata J, Hozawa A, Iwasaki M, Matsuda K, Minegishi N, Satoh M, Tanno K, Yamaji T, Wakai K, Hitomi J, Kiyohara Y, Kubo M, Tanaka H, Tsugane S, Yamamoto M, Sobue K, Shimizu A.
  • Journal Title: PLoS ONE Volume: 6 Issue: 1 Pages: 8018-8018
  • DOI: 10.1371/journal.pone.0147519
  • Peer Reviewed / Open Access
• [Journal Article] Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals (2015)
  • Author(s): Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, Yamaguchi-Kabata Y, Yokozawa J, Danjoh I, Saito S, Sato Y, Mimori T, Tsuda K, Saito R, Pan X, Nishikawa S, Ito S, Kuroki Y, Tanabe O, Fuse N, Kuriyama S, Kiyomoto H, Hozawa A, Minegishi N, Engel J D, Kinoshita K, Kure S, Yaegashi N, Yamamoto M.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 8018-8018
  • DOI: 10.1038/ncomms9018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Human GATA1 Gene Retains a 5' Insulator That Maintains Chromosomal Architecture and GATA1 Expression Levels in Splenic Erythroblasts. (2015)
  • Author(s): Moriguchi T, Yu L, Takai J, Hayashi M, Satoh H, Suzuki M, Ohneda K, Yamamoto M.
  • Journal Title: Mol Cell Biol. Volume: 35 Issue: 10 Pages: 1825-1837
  • DOI: 10.1128/mcb.00011-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. (2015)
  • Author(s): Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, Masue Imaizumi, Masayuki Yamamoto
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Issue: 39 Pages: 12169-12174
  • DOI: 10.1073/pnas.1509158112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progenitor stage-specific activity of a cis-acting double GATA motif for Gata1 gene expression (2015)
  • Author(s): Moriguchi T, Suzuki M, Yu L, Takai J, Ohneda K, and Yamamoto M. “
  • Journal Title: Mol Cell Biol Volume: 35 Issue: 5 Pages: 805-815
  • DOI: 10.1128/mcb.01011-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of GATA binding protein 2 levels via ubiquitin-dependent degradation by Fbw7: involvement of cyclin B-cyclin-dependent kinase 1-mediated phosphorylation of Thr176 in GATA binding protein 2. (2015)
  • Author(s): Nakajima T, Kitagawa K, Ohhata T, Sakai S, Uchida C, Shibata K, Minegishi N, Yumimoto K, Nakayama K-I, Masumoto K, Katou F, Niida H, Kitagawa M
  • Journal Title: J Biol Chem Volume: 290 Issue: 16 Pages: 10368-10381
  • DOI: 10.1074/jbc.m114.613018
  • Peer Reviewed / Open Access
• [Journal Article] Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population (2014)
  • Author(s): Motoike IN, Matsumoto M, Danjoh I, Katsuoka F, Kojima K, Nariai N, Sato Y, Yamaguchi-Kabata Y, Ito S, Kudo H, Nishijima I, Nishikawa S, Pan X, Saito R, Saito S, Saito T, Shirota M, Tsuda K, Yokozawa J, Igarashi K, Minegishi N, Tanabe O, Fuse N, Nagasaki M, Kinoshita K, Yasuda J, and Yamamoto M.
  • Journal Title: BMC Genomics Volume: 10 Issue: 1 Pages: 637-637
  • DOI: 10.1186/1471-2164-15-673
  • Peer Reviewed / Open Access
• [Journal Article] A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21 ; q26) by Activating EVI1 Expression (2014)
  • Author(s): Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, Yamamoto M.
  • Journal Title: Cancer Cell Volume: 25 Issue: 4 Pages: 415-427
  • DOI: 10.1016/j.ccr.2014.02.008
  • Peer Reviewed
• [Journal Article] Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis (2013)
  • Author(s): Suzuki N, Hirano I, Pan X, Minegishi N, Yamamoto M
  • Journal Title: Nature Commun Volume: 4 Issue: 1 Pages: 2902-2902
  • DOI: 10.1038/ncomms3902
  • Peer Reviewed
• [Journal Article] Plasticity of renal erythropoietin-producing cells governs fibrosis (2013)
  • Author(s): Souma T, Yamazaki S, Moriguchi T, Suzuki N, Hirano I, Pan X, Minegishi N, Abe M, Kiyomoto H, Ito S, Yamamoto M
  • Journal Title: J Am Soc Nephrol Volume: 24 Issue: 10 Pages: 1599-1616
  • DOI: 10.1681/asn.2013010030
  • Peer Reviewed / Open Access
• [Journal Article] A mouse model of adult-onset anaemia due to erythropoietin deficiency (2013)
  • Author(s): Yamazaki S, Souma T, Hirano I, Pan X, Minegishi N, Suzuki N, Yamamoto M
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1950-1950
  • DOI: 10.1038/ncomms2950
  • Peer Reviewed
• [Journal Article] Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia. (2013)
  • Author(s): Kon et al.
  • Journal Title: J. Clin. Invest. Volume: 123 Issue: 3 Pages: 1123-1137
  • DOI: 10.1172/jci63711
  • Peer Reviewed
• [Journal Article] Metabolic stress response implicated in diabetic retinopathy: The role of calpain, and the therapeutic impact of calpain inhibitor. (2012)
  • Author(s): Shanab AY, Nakazawa T, Ryu M, Tanaka Y, Himori N, Taguchi K, Ysuda M, Watanabe R, Takano J, Saido T, Minegishi N, Miyata T, Abe T, Yamamoto M.
  • Journal Title: Neurobiological Disease Volume: 48 Issue: 3 Pages: 556-557
  • DOI: 10.1016/j.nbd.2012.07.025
  • Peer Reviewed
• [Presentation] 東北メディカル・メガバンクの目標と進捗状況について (2016)
  • Author(s): 峯岸直子
  • Organizer: 放射線影響研究所ワークショップ（厚生労働省：丹羽班研究） 生物試料の保存と活用
  • Place of Presentation: 放射線影響研究所（ 広島県・広島市）
  • Year and Date: 2016-02-03
  • Invited
• [Presentation] 脳科学関連バイオリソースの整備・普及と調査研究-東北メディカル・メガバンクの現状と今後の展望 (2015)
  • Author(s): 峯岸直子
  • Organizer: 日本脳科学関連学会連合主催「脳科学の新しい推進プログラムに関する検討会」
  • Place of Presentation: 東京大学医学部鉄門記念講堂（ 東京都・文京区）
  • Year and Date: 2015-11-29
• [Presentation] The Biobank of Tohoku Medical Megabank Organization (2015)
  • Author(s): Minegishi N
  • Organizer: NHRI-ToMMo Conference, Genomics, biobanking, and Learning Health Systems
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-11-07
  • Int'l Joint Research / Invited
• [Presentation] Towards establishing a good biobanking system, survey on utilization of resources (2015)
  • Author(s): Nobukuni T, Suzuki K, Ogishima S, Toda S, Kudo H, Nishijima I, Terakawa T, Arai T, Yamamoto M, Minegishi N
  • Organizer: ESBB LONDON 2015
  • Place of Presentation: London, UK
  • Year and Date: 2015-09-29
  • Int'l Joint Research
• [Presentation] Avilability of Records on Blood Collection and Transportation Influences Reliability of Omics Analysis (2015)
  • Author(s): Saigusa D, Katoh Y, Koshiba S, Minegishi N , Kudo H, Nishijima I, Nobukuni T, Terakawa T, Tanabe O, Yamamoto M
  • Organizer: HANDSON BIOBANK 2015
  • Place of Presentation: Milano, Italy
  • Year and Date: 2015-07-30
  • Int'l Joint Research
• [Presentation] Assessment of ID Integrity with ABO blood typing from Questionnaire to Genomic Data in Japanese Biobank: ToMMo (2015)
  • Author(s): Kudo H, Nishijima I, Terakawa T, Nobukuni T, Saito S, Ogishima S, Katsuoka F, Nagasaki M, Yasuda J, Minegishi N, Yamamoto M
  • Organizer: ISBER (International Society for Biological and Environmental Repositories)2015 Annual meeting and exhibit
  • Place of Presentation: Phoenix, AZ, USA
  • Year and Date: 2015-05-05
  • Int'l Joint Research
• [Presentation] ToMMo Biobank System for ensuring the quality and accuracy of biospecimens. (2015)
  • Author(s): Minegishi N
  • Organizer: A Health Informatics Infrastructure for a Mew Era. The Learning Health System & Tohoku Medical Information Highway
  • Place of Presentation: Tohoku University, Sendai
  • Year and Date: 2015-02-23 – 2015-02-25
• [Presentation] 東北メディカル・メガバンク機構のバイオバンクの管理体制． (2015)
  • Author(s): 峯岸直子
  • Organizer: 放射線影響研究所ワークショップ 生物資料の保存と利用
  • Place of Presentation: 放射線影響研究所講堂、広島
  • Year and Date: 2015-02-17
  • Invited
• [Presentation] 宮城・岩手両県の健常人コホート研究の基盤となるバイオバンク構築の現状と今後． (2015)
  • Author(s): 峯岸直子
  • Organizer: 第1回ヒト生体試料科学研究会シンポジウム バイオバンクの現状と今後
  • Place of Presentation: 国立がん研究センター築地キャンパス，東京
  • Year and Date: 2015-01-19
  • Invited
• [Presentation] 東北メディカル・メガバンク機構における生体試料の管理 (2015)
  • Author(s): 峯岸直子
  • Organizer: 第2回JMACシンポジウムサテライトワークショップ，バイオバンク活用に向けた生体試料品質を考える．国際標準化の動きと将来に向けての日本の取り組み
  • Place of Presentation: TKP東京駅前カンファレンスセンター，東京
  • Year and Date: 2015-01-08
  • Invited
• [Presentation] Biobank Construction based on cohort studies after the seismic disaster of 2011. (2014)
  • Author(s): Minegishi N
  • Organizer: Karolinska-Tohoku Joint Symposium on Medical Sciences
  • Place of Presentation: Tohoku University, Sendai
  • Year and Date: 2014-11-08 – 2014-11-09
• [Presentation] Biobank Construction after Earthquake and Tsunami Disaster in Japan. (2014)
  • Author(s): Minegishi N, Kudo H, Nishijima I, Hozawa A, Kuriyama S, Tanno K, Sasaki R, Takai T, Ogishima S, Kiyomoto H, Satoh M, Hachiya T, Shiwa Y, Shimizu A, Hitomi J, Yaegashi N, Sobue K, Yamamoto M.
  • Organizer: International Society of Biological and Environmental Repositories
  • Place of Presentation: Orlando, Florida
  • Year and Date: 2014-05-20 – 2014-05-24
• [Presentation] Biobank Project of Tohoku Medical Megabank Organization (2013)
  • Author(s): Naoko Minegishi
  • Organizer: 2th Osong International Bio-Symposium
  • Place of Presentation: KINTEX, Goyang, Korea
  • Invited
• [Presentation] トランスジェニックマウスを利用したエリスロポエチン遺伝子エンハンサーの探索. (2013)
  • Author(s): 平野育生、鈴木教郎、山㟢瞬、峯岸直子、山本雅之、清水律子.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド、兵庫
• [Presentation] クラスリン小胞体形成因子SMAP1の欠損は細胞内小胞輸送の異常をきたし、骨髄異形成症候群を誘引する． (2012)
  • Author(s): 昆俊亮，峯岸直子，田邉憲次，渡邊利雄，船木智，坂本大輔，樋口雄大，清成 寛、浅野克敏、福本学、真田昌、小川誠司、中村卓郎、佐竹正延
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] 神経堤細胞におけるエリスロポエチン遺伝子発現． (2012)
  • Author(s): 平野育生，鈴木教郎，潘小青，峯岸直子，山本雅之
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
• [Presentation] エリスロポエチン産生細胞特異的Cre発現マウスの樹立と解析． (2012)
  • Author(s): 山㟢瞬，峯岸直子，鈴木教郎，山本雅之．
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
• [Book] メディカルサイエンス臨床化学検査学, I. 生命現象の生化学4. 情報の流れ (2014)
  • Author(s): 峯岸 直子
  • Total Pages: 11
  • Publisher: 近代出版