Transcriptional coactivator MED1, type 2 innate immunity and metabolism

• Project/Area Number: 20K07782
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kobe University
• Principal Investigator: Ito Mitsuhiro 神戸大学, 保健学研究科, 教授 (50362794)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 転写メディエーター / MED1 / 核内受容体 / 2型自然免疫 / メディエーター / 基本転写共役因子複合体 / 自然免疫

Outline of Research at the Start

2型自然免疫は内臓白色脂肪組織のベージュ化を誘導する。私達は基本的転写共役複合体
メディエーターを発見し、そのMED1サブユニットが核内受容体のコアクチベーターであり脂肪形成に必須なことを報告した。またMED1の核内受容体結合能を破壊したマウスを作製し、MED1の核内受容体結合能が果たす生理的役割を調べる動物モデルを確立している。本研究では、本マウスの生理学的解析のうち、自然免疫、特に2型自然免疫の状態と白色脂肪組織の代謝機能を解析に焦点を絞って、MED1と核内受容体との結合がこれらに与える役割を検証する。

Outline of Final Research Achievements

Mediator, composed of multiple proteins, is crucial for gene activations in animal cells. One of the Mediator components MED1 employs the activation of the functions of receptors for lipophilic hormones such as female hormone. When we generated mutant mice, where the interactions between lipophilic hormone receptors and MED1 were impaired, these mice grew normally. However, these mice did not get as obese as normal mice when they were fed with high-calory diet. The present study provides a possibility that the mechanism relies on the so-called natural immunity system that mammals have. Namely, in the fat tissues of these mutant mice, a variety of cells that employs the natural immunity were induced and activated, and these mice showed resistance to obesity. Hence, the importance of MED1 in the fat metabolism has been proposed.

Academic Significance and Societal Importance of the Research Achievements

厚労省「国民健康・栄養調査」によれば、日本国民の成人男性33.0%、女性22.3%が肥満であり、その数は年々増加している。飽食の現代、高エネルギー食に伴う肥満をいかに解消するかは公衆衛生上非常に重要な課題になっている。本研究はこの課題に、基本的な遺伝子活性化のメカニズムからユニークに取り組む点で学術的意義がある。本研究の重要で都合いい点は、MED1と脂溶性ホルモン受容体との連関を断絶しても通常の生活に影響を与えず、過食時に限って肥満や代謝悪化を抑制することであり、将来ヒトに適用できれば肥満の治療や予防に有効な可能性が期待される。

Research Products

• [Int'l Joint Research] ロックフェラー大学(米国)
• [Int'l Joint Research] ロックフェラー大学(米国)
• [Journal Article] Promising Efficacy of a Third Dose of mRNA SARS-CoV-2 Vaccination in Patients Treated with Anti-CD20 Antibody Who Failed 2-Dose Vaccination (2022)
  • Author(s): Funakoshi Y, Yakushijin K, Ohji G, Hojo W, Sakai H, Watanabe M, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Koyama T, Imamura Y, Kiyota N, Matsuoka H, Mori Y, Minami H
  • Journal Title: Vaccines Volume: 10 Issue: 6 Pages: 965-965
  • DOI: 10.3390/vaccines10060965
  • Peer Reviewed / Open Access
• [Journal Article] A Third Dose COVID-19 Vaccination in Allogeneic Hematopoietic Stem Cell Transplantation Patients (2022)
  • Author(s): Watanabe M, Yakushijin K, Funakoshi Y, Ohji G, Ichikawa H, Sakai H, Hojo W, Saeki M, Hirakawa Y, Matsumoto S, Sakai R, Nagao S, Kitao A, Miyata Y, Koyama T, Saito Y, Kawamoto S, Yamamoto K, Ito M, Murayama T, Matsuoka H, Minami H
  • Journal Title: Vaccines Volume: 10 Issue: 11 Pages: 1830-1830
  • DOI: 10.3390/vaccines10111830
  • Peer Reviewed / Open Access
• [Journal Article] Global longitudinal strain is superior to ejection fraction for long‐term follow‐up after allogeneic hematopoietic stem cell transplantation (2022)
  • Author(s): Watanabe M, Yakushijin K, Tanaka H, Chijiki R, Saeki M, Hirakawa Y, Takakura H, Usui Y, Ichikawa H, Sakai R, Matsumoto S, Nagao S, Mizutani Y, Kurata K, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Matsuoka H, Minami H
  • Journal Title: eJHaem Volume: 4 Issue: 1 Pages: 192-198
  • DOI: 10.1002/jha2.586
  • Peer Reviewed / Open Access
• [Journal Article] Limited increase in antibody titers following mRNA SARS-CoV-2 vaccination for more than 3 years after final dose of anti-CD20 antibody (2022)
  • Author(s): Funakoshi Y, Yakushijin K, Ohji G, Hojo W, Sakai H, Watanabe M, Saeki M, Hirakawa Y, Sakai R, Matsumoto S, Mizutani Y, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Nishimura M, Imamura Y, Kiyota N, Matsuoka H, Mori Y, Minami H.
  • Journal Title: Int J Hematol Volume: 115 Issue: 1 Pages: 7-10
  • DOI: 10.1007/s12185-021-03247-y
  • Peer Reviewed
• [Journal Article] The Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Japanese Patients after Allogeneic Stem Cell Transplantation (2022)
  • Author(s): Watanabe M, Yakushijin K, Funakoshi Y, Ohji G, Hojo W, Sakai H, Saeki M, Hirakawa Y, Matsumoto S, Sakai R, Nagao S, Kitao A, Miyata Y, Koyama T, Saito Y, Kawamoto S, Ito M, Murayama T, Matsuoka H, Minami H.
  • Journal Title: Vaccines Volume: 10 Issue: 2 Pages: 158-158
  • DOI: 10.3390/vaccines10020158
  • Peer Reviewed
• [Journal Article] Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4 (2020)
  • Author(s): Kana Kuronuma, Aya Yokoi, Tomoya Fukuoka, Muneaki Miyata, Akio Maekawa, Satowa Tanaka, Leo Matsubara, Chie Goto, Miki Matsuo, Hao-Wei Han, Mai Tsuruta, Haruka Murata, Hikari Okamoto, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Journal Title: Heliyon Volume: 6 Issue: 4 Pages: 03743-03743
  • DOI: 10.1016/j.heliyon.2020.e03743
  • NAID: 120006844969
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Detection of a novel CBFB-MYH11 fusion transcript in acute myeloid leukemia M1 with inv(16)(p13q22). (2020)
  • Author(s): Kurata K, Yamamoto K, Okazaki Y, Noguchi Y, Matsui K, Matsumoto H, Inui Y, Yakushijin K, Ito M, Nakamachi Y, Matsuoka H, Saegusa J, Minami H.
  • Journal Title: Cancer Genet Volume: 241 Pages: 72-76
  • DOI: 10.1016/j.cancergen.2019.07.005
  • NAID: 120006818788
  • Peer Reviewed
• [Journal Article] MYC amplification on double minute chromosomes in plasma cell leukemia with double IGH/CCND1 fusion genes. (2020)
  • Author(s): Yamamoto K, Yakushijin K, Ito M, Goto H, Higashime A, Kajimoto K, Hayashi Y, Matsuoka H, Minami H
  • Journal Title: Cancer Genet Volume: 242 Pages: 35-40
  • DOI: 10.1016/j.cancergen.2020.01.049
  • NAID: 120006823972
  • Peer Reviewed
• [Journal Article] Disseminated cryptococcosis resembling miliary tuberculosis in a patient with acute myeloid leukemia (2020)
  • Author(s): Kurata K, Nishimura S, Higashime A, Kawaguchi K, Nagao S, Kozuki Y, Sai S, Yakushijin K, Yamamoto K, Ito M, Matsuoka H, Minami H
  • Journal Title: J Infect Chemother Volume: 26 Issue: 11 Pages: 1216-1219
  • DOI: 10.1016/j.jiac.2020.07.004
  • Peer Reviewed
• [Journal Article] Lymphoplasmacytic lymphoma in a patient with Birt-Hogg-Dube syndrome (2020)
  • Author(s): Kurata K, Matsumoto H, Jimbo N, Yakushijin K, Yamamoto K, Ito M, Nakamachi Y, Matsuoka H, Saegusa J, Seyama K, Itoh T, Minami H
  • Journal Title: Int J Hematol Volume: 112 Issue: 6 Pages: 864-870
  • DOI: 10.1007/s12185-020-02970-2
  • NAID: 120006919996
  • Peer Reviewed
• [Journal Article] Translin restricts the growth of pubertal mammary epithelial cells estrogen-independently in mice. (2019)
  • Author(s): Matsubara L, Fukuoka T, Sudo K, Fukunaga T, Imanishi A, Kuronuma K, Matsuo M, Kamoshida S, Hasegawa N, Asano S, Ito M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 521 Issue: 3 Pages: 562-568
  • DOI: 10.1016/j.bbrc.2019.10.176
  • NAID: 120006784500
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Promising Efficacy of a Third Dose of mRNA SARS-CoV-2 Vaccination in Patients Treated with Anti-CD20 Antibody Who Failed 2-Dose Vaccination (2023)
  • Author(s): Funakoshi Y, Yakushijin K, Ohji G, Hojo W, Sakai H, Watanabe M, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Koyama T, Imamura Y, Kiyota N, Matsuoka H, Mori Y, Minami H
  • Organizer: 第20回日本臨床腫瘍学会学術集会
• [Presentation] A third dose COVID-19 vaccination in allogeneic stem cell transplantation patients (2022)
  • Author(s): Watanabe M, Yakushijin K, Funakoshi Y, Ohji G, Sakai H, Hojo W, Saeki M, Hirakawa Y, Matsumoto S, Ichikawa H, Sakai R, Nagao S, Kitao A, Miyata Y, Koyama T, Saito Y, Kawamoto S, Ito M, Murayama T, Matsuoka H, Minami H
  • Organizer: 27th Annual Meeting of Asia-Pacific Blood and Marrow Transplantation Group
  • Int'l Joint Research
• [Presentation] MED1 nuclear receptor recognition motifs decides breast carcinoma cell growth (2022)
  • Author(s): 大橋侑加、隅田結衣、村中杏優、田邉匠、Roeder RG、長谷川菜摘、伊藤光宏
  • Organizer: 第45 回日本分子生物学会年会
• [Presentation] 造血幹細胞移植患者における3回目のCOIVD-19mRNAワクチンの有効性 (2022)
  • Author(s): 渡部まりか、藥師神公和、船越洋平、大路剛、市川大哉、酒井博則、北條渉、佐伯美紀、平川結梨、松本咲耶、坂井里奈、長尾茂輝、北尾章人、宮田吉晴、伊藤光宏、松岡広、南博信
  • Organizer: 第45回日本造血・免疫細胞療法学会総会
• [Presentation] Limited Increase in Antibody Titers following mRNA SARS-CoV-2 Vaccination for More than 3 Years after Final Dose of Anti-CD20 Antibody (2022)
  • Author(s): Yohei Funakoshi, Kimikazu Yakushijin, Goh Ohji, Wataru Hojo, Hironori Sakai, Marika Watanabe, Miki Saeki, Yuri Hirakawa, Rina Sakai, Sakuya Matsumoto, Yu Mizutani, Akihito Kitao, Yoshiharu Miyata, Yasuyuki Saito, Shinichiro Kawamoto, Katsuya Yamamoto, Mitsuhiro Ito, et al
  • Organizer: 第19回日本臨床腫瘍学会学術集会
• [Presentation] Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in Japanese patients after allogeneic stem cell transplantation (2022)
  • Author(s): Marika Watanabe, Kimikazu Yakushijin, Yohei Funakoshi, Goh Ohji, Hironori Sakai, Wataru Hojo, Miki Saeki, Yuri Hirakawa, Sakuya Matsumoto, Rina Sakai, Shigeki Nagao, Akihito Kitao, Yoshiharu Miyata, Taiji Koyama, Yasuyuki Saito, Shinichiro Kawamoto, Mitsuhiro Ito, Tohru Murayama, Hiroshi Matsuoka, Hironobu Minami
  • Organizer: 48th EBMT Annual Meeting
  • Int'l Joint Research
• [Presentation] Mediator subunit MED1 restricts type 2 innate immunity in adipose tissue (2021)
  • Author(s): Mizuha Anamoto, Ayaka Fujiwara, Fumi Tatsuno, Moeki Onishi, Mai Tsuruta, Haruka Murata, Takumi Tanabe, Rino Kishida, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] A model for multifaceted interaction of GATA1 with Mediator transcriptional coregulatory complex (2021)
  • Author(s): Mana Morikawa, Kafu Yasui, Naoya Kanada, Hikari Okamoto, Yuuka Ohashi, Takumi Kajitani, Yui Sumida, Tomoya Fukuoka, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Mediator subunit MED1 restricts type 2 innate immunity in visceral adipose tissue (2021)
  • Author(s): Ayaka Fujiwara, Mizuha Anamoto, Moeki Onishi, Fumi Tatsuno, Hikari Okamoto, Mai Tsuruta, Haruka Murata, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] Multifaceted interaction of GATA1 with Mediator: a novel model for GATA1-induced transcriptional activation (2021)
  • Author(s): Kafu Yasui, Mana Morikawa, Mizuha Anamoto, Naoya Kanada, Hikari Okamoto, Takumi Kajitani, Yuuka Ohashi, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 同種造血幹細胞移植前後のGlobal Longitudinal Strain（GLS）による長期的な心機能評価と心機能改善への可能性 (2021)
  • Author(s): 渡部 まりか，藥師神 公和，田中 秀和，千々木 瑠里，佐伯 美紀，平川 結梨，高倉 嗣丈，臼井 佑太郎，坂井 里奈，松本 咲耶，水谷 優，北尾 章人，長尾 茂輝，宮田 吉晴，斎藤 泰之，川本 晋一郎，山本 克也，伊藤 光宏，松岡 広，南 博信
  • Organizer: 第4回日本腫瘍循環器学会学術集会
• [Presentation] 転写メディエーターのサブユニットMED1によるエストロゲン受容体αの乳癌細胞核への局在 (2021)
  • Author(s): 金田直也、大橋侑加、隅田結衣、森川真名、鶴田真衣、村田晴佳、田邉匠、Robert G. Roeder、長谷川菜摘、伊藤光宏
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] Increase in antibody titers following SARS-CoV-2 vaccination remains limited for more than 3 years after final dose of anti-CD20 antibody (2021)
  • Author(s): Yohei Funakoshi, Kimikazu Yakushijin, Goh Ohji, Wataru Hojo, Hironori Sakai, Marika Watanabe, Miki Saeki, Yuri Hirakawa, Rina Sakai, Sakuya Matsumoto, Yu Mizutani, Akihito Kitao, Yoshiharu Miyata, Yasuyuki Saito, Shinichiro Kawamoto, Katsuya Yamamoto, Mitsuhiro Ito, et al
  • Organizer: 63rd Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Global longitudinal strain is superior to the ejection fraction for long-term follow-up after allogeneic hematopoietic stem cell transplantation (2021)
  • Author(s): Marika Watanabe, Kimikazu Yakushijin, Hidekazu Tanaka, Ruri Chijiki, Miki Saeki, Yuri Hirakawa, Hidetomo Takakura, Yutaro Usui, Rina Sakai, Sakuya Matsumoto, Yu Mizutani, Akihito Kitao, Shigeki Nagao, Yoshiharu Miyata, Yasuyuki Saito, Shinichiro Kawamoto, Katsuya Yamamoto, Mitsuhiro Ito, et al
  • Organizer: 63rd Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] MGP maintains myeloid leukemic stem/progenitor cells by modulating BMP type I receptors ALK2/ALK3 (2020)
  • Author(s): Hikari Okamoto, Mai Tsuruta, Haruka Murata, Tomoya Fukuoka, Mana Morikawa, Takumi Kajitani, Kafu Yasui, Ayano Isshiki, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Nuclear receptor binding of MED1 is critical for type 2 innate immunity in visceral adipose tissue (2020)
  • Author(s): Rino Kishida, Tomoya Fukuoka, Kyo Saiki, Mizuha Anamoto, Hikaru Tsutsumi, Manami Tsuji, Naoya Kanada, Ayaka Fujiwara, Yuuka Ohashi, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Relative dose intensity of CHOP regimen for aggressive lymphoma patients: A retrospective study at Kobe University Hospital (2020)
  • Author(s): Yoshiharu Miyata, Kimikazu Yakushijin, Marika Watanabe, Rina Sakai, Hideaki Goto, Yu Mizutani, Yasuyuki Saito, Shinichiro Kawamoto, Mitsuhiro Ito, Hiroshi Matsuoka, Hironobu Minami
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] MED1 restricts type 2 innate immunity in visceral adipose tissue through its LxxLL nuclear receptor binding motifs (2020)
  • Author(s): Kyo Saiki, Rino Kishida, Tomoya Fukuoka, Mizuha Anamoto, Ayaka Fujiwara, Manami Tsuji, Hikaru Tsutsumi, Naoya Kanada, Yuuka Ohashi, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] MGP maintains myeloid leukemia initiating cells through BMP type I receptors ALK2/ALK3 (2020)
  • Author(s): Hikari Okamoto, Mai Tsuruta, Haruka Murata, Takumi Kajitani, Tomoya Fukuoka, Mana Morikawa, Kafu Yasui, Ayano Isshiki, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Organizer: 第43回日本分子生物学会年会
• [Remarks]
  • URL: http://www2.kobe-u.ac.jp/~itomi/