The active chromatin domain that is regulated by the non-coding RNAs in recurrent breast cancer

• Project/Area Number: 16H04744
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Molecular biology
• Research Institution: Japanese Foundation for Cancer Research (2017-2018); Kumamoto University (2016)
• Principal Investigator: Saitoh Noriko 公益財団法人がん研究会, がん研究所 がん生物部, 部長 (40398235)
• Research Collaborator: YAMAMOTO tatsuro ; SAKAMOTO chiyomi ; TACHIWANA hiroaki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 非コードRNA / クロマチン / 細胞核 / 乳がん / クロマチンドメイン / 核内非コードRNA / ESR1 / RNA / 核内構造 / レスベラトロール

Outline of Final Research Achievements

Approximately 70% of breast cancers is estrogen receptor (ER)-positive, which highly express the ER protein. The endocrine therapy that inhibits estrogenic action is effective for this type of breast cancer, however, the cancer acquires the therapy resistance after long term of the treatment, resulting in recurrence. In this study, using the endocrine-therapy resistant breast cancer cell model, I have revealed a molecular mechanism underlying the overexpression of ESR1, the gene for ER during the acquisition of the therapy resistance. I found that the non-coding RNAs, Eleanors regulate the mega-base chromatin domain and expression of the multiple genes involving breast cancer including ESR1.

Academic Significance and Societal Importance of the Research Achievements

遺伝子の発現制御はほぼ全ての生命現象に重要で、その異常はがんを含む疾患に深く関わる。本研究成果では、乳がんに重要なESR1遺伝子の発現が非コードRNAエレノアによるクロマチンドメインの制御を介して行われるという、学術的に新しい知見を得られた。また、非コードRNAを標的とする再発乳がんの診断や治療への道筋をつける成果を得た。

Research Products

• [Int'l Joint Research] Univ of Massachusetts Med Sch/Mindshare Medical Inc(米国)
• [Int'l Joint Research] Harbin Medical University(中国)
• [Int'l Joint Research] NIA, NIH(米国)
• [Int'l Joint Research] Harbin Medical University(中国)
• [Journal Article] Ki-67 and condensins support the integrity of mitotic chromosomes through distinct mechanisms (2018)
  • Author(s): Takagi Masatoshi、Ono Takao、Natsume Toyoaki、Sakamoto Chiyomi、Nakao Mitsuyoshi、Saitoh Noriko、Kanemaki Masato T.、Hirano Tatsuya、Imamoto Naoko
  • Journal Title: Journal of Cell Science Volume: 131 Pages: 212092-212092
  • DOI: 10.1242/jcs.212092
  • Peer Reviewed / Open Access
• [Journal Article] An asymmetric centromeric nucleosome (2018)
  • Author(s): Ichikawa Yuichi、Saitoh Noriko、Kaufman Paul D
  • Journal Title: eLife Volume: 7
  • DOI: 10.7554/elife.37911
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endocrine therapy-resistant breast cancer model cells are inhibited by soybean glyceollin I through Eleanor non-coding RNA (2018)
  • Author(s): Yamamoto Tatsuro、Sakamoto Chiyomi、Tachiwana Hiroaki、Kumabe Mitsuru、Matsui Toshiro、Yamashita Tadatoshi、Shinagawa Masatoshi、Ochiai Koji、Saitoh Noriko、Nakao Mitsuyoshi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15202-15202
  • DOI: 10.1038/s41598-018-33227-y
  • Peer Reviewed / Open Access
• [Journal Article] The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling. (2017)
  • Author(s): Tanaka, H., Takebayashi S. I., Sakamoto, A., Igata, T., Nakatsu, Y., Saitoh, N., Hino, S., and Nakao, M.
  • Journal Title: Cell Rep. Volume: 18 Issue: 9 Pages: 2148-2161
  • DOI: 10.1016/j.celrep.2017.02.021
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of estrogen receptor beta gene methylation in autistic males in a Chinese Han population (2017)
  • Author(s): Wang, X., Liang, S., Sun, Y., Li, H., Endo, F., Nakao, M., Saitoh, N.* and Wu, L.*
  • Journal Title: Metab Brain Dis Volume: - Issue: 4 Pages: 1033-1042
  • DOI: 10.1007/s11011-017-9990-7
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Condensin II plays an essential role in reversible assembly of mitotic chromosomes in situ (2017)
  • Author(s): Ono Takao、Sakamoto Chiyomi、Nakao Mitsuyoshi、Saitoh Noriko、Hirano Tatsuya
  • Journal Title: Molecular Biology of the Cell Volume: 28 Issue: 21 Pages: 2875-2886
  • DOI: 10.1091/mbc.e17-04-0252
  • Peer Reviewed / Open Access
• [Journal Article] The 4D nucleome in Krak?w - Prospects for an emerging field (2017)
  • Author(s): Dobrucki Jurek、Saitoh Noriko
  • Journal Title: Nucleus Volume: 8 Issue: 5 Pages: 447-448
  • DOI: 10.1080/19491034.2017.1347243
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Roles of long non-coding RNAs in chromosome domains (2016)
  • Author(s): Tomita, S., Abdalla, M. O. A., Fujiwara, S., Yamamoto, T., Iwase, H., Nakao, M. and Saitoh, N.*.
  • Journal Title: WIREs RNA Volume: - Issue: 2 Pages: 30366-30374
  • DOI: 10.1002/wrna.1384
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nuclear extrusion precedes discharge of genomic DNA fibers during tunicamycin-induced neutrophil extracellular trap-osis (NETosis)-like cell death in cultured human leukemia cells (2016)
  • Author(s): Nakayama, T., Saitoh, N, Morotomi-Yano, K., Yano, K.I., Nakao, M, Saitoh, H
  • Journal Title: Cell Biol Int Volume: 印刷中 Issue: 5 Pages: 597-602
  • DOI: 10.1002/cbin.10594
  • Peer Reviewed
• [Journal Article] Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli (2016)
  • Author(s): Matsumoto A, Sakamoto C, Matsumori H, Katahira J, Yasuda Y, Yoshidome K, Tsujimoto M, Goldberg IG, Matsuura N, Nakao M, Saitoh S, Hieda M
  • Journal Title: Nucleus Volume: 7(1) Issue: 1 Pages: 68-83
  • DOI: 10.1080/19491034.2016.1149664
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Nuclear non-coding RNAs Eleanors, define the active ESR1 chromatin domain in breast cancer cells. (2018)
  • Author(s): Saitoh, N.
  • Organizer: Cold Spring Harbor Conferences Asia, RNA Biology.
  • Int'l Joint Research / Invited
• [Presentation] Saitoh, N. Chromatin regulation by nuclear non-coding RNA in breast cancer cells. (2018)
  • Author(s): Saitoh, N.
  • Organizer: HiHA 国際ワークショップ ?染色体動態、分配と機能の理解に向かって
  • Int'l Joint Research / Invited
• [Presentation] 乳がんの高次クロマチンドメインに関わるノンコーディングRNA. (2018)
  • Author(s): 斉藤典子
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] 乳がんに関わるノンコーディングRNAと細胞核内ゲノム構造. (2018)
  • Author(s): 斉藤 典子
  • Organizer: 千葉大学 第16回クロマチン代謝制御セミナー
  • Invited
• [Presentation] 再発乳がんの活性染色体ドメインに関わるエレノアノンコーディングRNA (2018)
  • Author(s): 斉藤典子
  • Organizer: 第２回富山RNAワークショップ
  • Invited
• [Presentation] 乳がんと細胞核のかたち (2018)
  • Author(s): 斉藤典子
  • Organizer: 新学術領域「動的クロマチン構造と機能」一般公開シンポジウム 遺伝子研究の最前線
  • Invited
• [Presentation] A cluster of nuclear long non-coding RNAs defines an active chromatin domain in recurrent breast cancer cells (2017)
  • Author(s): Saitoh, N.
  • Organizer: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology Seminar
  • Int'l Joint Research / Invited
• [Presentation] Non-coding RNAs involved in active chromatin domain in breast cancer. (2017)
  • Author(s): Yamamoto, T., Abdalla, M.O., Fujiwara, S., Tomita, S., Nakao, M., and Saitoh, N.
  • Organizer: HMGU-Japan Epigenetics and Chromatin Symposium
  • Int'l Joint Research / Invited
• [Presentation] Eleanor non-coding RNA defines the active ESR1 chromatin domain in breast cancer recurrence. (2017)
  • Author(s): Saitoh, N.
  • Organizer: 43rd Naito Conference on “Noncoding RNA: Biology, Disease, & Chemistry”
  • Int'l Joint Research / Invited
• [Presentation] Active topologically associating domain is formed with non-coding RNA Eleanors in the breast cancer nucleus (2017)
  • Author(s): Yamamoto, T., Abdalla, MO., Nakao, M., and Saitoh, N.
  • Organizer: Second international meeting on SMC proteins
  • Int'l Joint Research
• [Presentation] A cluster of non-coding RNAs, Eleanors determine the active chromatin domain in breast cancer. (2017)
  • Author(s): Yamamoto, T., Abdalla, MO. Fujiwara, S., Tomita, S., Nakao,M., and Saitoh, N
  • Organizer: 4D Nucleome: The Cell Nucleus in Space and Time
  • Int'l Joint Research / Invited
• [Presentation] 活性染色体ドメインに関する核内長鎖ノンコーディングRNA. (2017)
  • Author(s): 斉藤典子、山本達郎、モハメドオサマアブダラ、藤原沙織、冨田さおり、前原一満、大川恭行、立和名博昭、中尾光善.
  • Organizer: 生命科学系学会合同年次大会
  • Invited
• [Presentation] Non-coding RNAs involved in active chromatin domain formation in breast cancer (2017)
  • Author(s): Saitoh, N.
  • Organizer: Seminar at Division of Biological Science
  • Invited
• [Presentation] Eleanor non-coding RNAs form the active chromatin domain in breast cancer recurrence. (2017)
  • Author(s): Saitoh,N., Yamamoto, T., Fujiwara, S., Tomita，S. and Nakao, M.
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Invited
• [Presentation] エピジェネティクスに関わるノンコーディングRNA Eleanor (2017)
  • Author(s): 斉藤 典子
  • Organizer: 第５回X染色体研究会
• [Presentation] 乳がんエピジェネティクスに関わる核内長鎖ノンコーディングRNA (2017)
  • Author(s): 斉藤 典子
  • Organizer: 千葉県がんセンター集談会
  • Invited
• [Presentation] Formation of the membrane-less nuclear organelle, the nucleolus. (2017)
  • Author(s): Saitoh, N., Matsumori, H., Haraguchi, T., Ito. Y., Tokunaga, M., Sogawa, K., Nakao, M.
  • Organizer: The 40th Annual Meeting of the Japan neuroscience Society
  • Invited
• [Presentation] 核小体の構造維持と物性に関わる60Sリボソームタンパク質 (2017)
  • Author(s): 斉藤典子
  • Organizer: 日本大学文理学部生命科学科セミナー
  • Invited
• [Presentation] 乳がん細胞でノンコーディングRNA群により規定される活性染色体ドメイン (2017)
  • Author(s): 斉藤典子、山本達郎、モハメドオサマアブダラ、藤原沙織、冨田さおり、前原一満、大川恭行、中尾光善.
  • Organizer: 第11回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] Nuclear domains implicated in gene regulations and diseases: the nucleolus and RNA clouds. (2017)
  • Author(s): Noriko Saitoh
  • Organizer: 第735回 生医研セミナー
  • Invited
• [Presentation] 乳がんにおいて非コードRNA群が規定する活性染色体ドメイン (2016)
  • Author(s): 斉藤典子、モハメドオサマアブダラ、藤原沙織、山本達郎、冨田さおり、前原一満、大川恭行、中尾光善.
  • Organizer: 第39回日本分子生物学会年会 シンポジウム1AS13「発生・老化・疾患をつかさどるクロマチンイベント」
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] ER陽性乳がんにおけるエレノアドメインのダイナミックなクロマチン制御 (2016)
  • Author(s): 山本達郎、前原一満、大川恭行、三浦尚、平谷伊智朗、斉藤典子、中尾光善
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] 機械学習画像解析ウインチャームによる胃がん組織の判別 (2016)
  • Author(s): 安田洋子、徳永和明、坂本智代美、斉藤典子、中尾光善
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] 非コードRNAにより規定されるクロマチンドメイン (2016)
  • Author(s): 斉藤典子、モハメドオサマアブダラ、藤原沙織、山本達郎、冨田さおり、前原一満、大川恭行、中尾光善.
  • Organizer: 遺伝研研究会「クロマチン・細胞核の動的構造変換とエピジェネティック制御」
  • Place of Presentation: 静岡県 三島市 遺伝学研究所
  • Year and Date: 2016-10-27
  • Invited
• [Presentation] BRD4はMMP2のエピジェネティックな調節を介して口腔扁平上皮癌の転移に関与する (2016)
  • Author(s): 山本達郎、廣末晃之、中元雅史、吉田遼司、川原健太、永田将士、田中拓也、斉藤典子、中尾光善、中山秀樹
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] 乳がんの治療耐性獲得に関わる核内非コードRNAエレノア (2016)
  • Author(s): 斉藤典子、モハメドオサマアブダラ、藤原沙織、山本達郎、冨田さおり、前原一満、大川恭行、中尾光善
  • Organizer: 第89回日本生化学会大会 シンポジウム1S15「疾患における細胞核・クロマチンの動態変動 」
  • Place of Presentation: 宮城県 仙台市 東北大学川内北キャンパス
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] siRNA ハイコンテントスクリーニングによる細胞核構築の解析 (2016)
  • Author(s): 斉藤典子、松森はるか、安田洋子、坂本智代美、檜枝美紀、Ilya G Goldberg、中尾光善
  • Organizer: バイオイメージ・インフォーマティクス ワークショップ2016
  • Place of Presentation: 大阪府 吹田 大阪大学 吹田キャンパス 銀杏会館
  • Year and Date: 2016-06-23
  • Invited
• [Presentation] パターン認識プログラムと細胞核形態に着目した癌組織の定量化 (2016)
  • Author(s): 安田洋子、徳永和明、坂本智代美、斉藤典子、中尾光善
  • Organizer: バイオイメージ・インフォマティクスワークショップ2016
  • Place of Presentation: 大阪府 吹田市 大阪大学吹田キャンパス
  • Year and Date: 2016-06-22
• [Presentation] Nuclear structures for gene regulation: the nucleolus and RNA clouds (2016)
  • Author(s): Saitoh, N.
  • Organizer: NIA/NIH seminar
  • Place of Presentation: NIA/NIH, Bethesda, Maryland, USA
  • Year and Date: 2016-05-09
  • Int'l Joint Research / Invited
• [Presentation] Machine learning image analysis reveals structural roles of ribosomal proteins in the nucleolus and Diamond-Blackfan anemia (2016)
  • Author(s): Matsumori, H., Osakada, H., Haraguchi, T., Ito, E., Goldberg, I.G., Nakao, M., and Saitoh, N.
  • Organizer: Cold Spring Harbor Laboratory Meeting; Nuclear organization & function
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
  • Year and Date: 2016-05-03
  • Int'l Joint Research
• [Book] 「実験医学」増刊 第36巻第17号、平野達也・胡桃坂仁志 編 「染色体の新常識」 (2018)
  • Author(s): 野澤竜介、斉藤典子
  • Publisher: 羊土社
• [Book] 基礎分子生物学II : 遺伝子発現制御機構 田村隆明・浦聖惠編 編 (2017)
  • Author(s): 山本達郎、中尾光善、斉藤典子
  • Publisher: 東京化学同人
• [Book] 核内イベントの時空間制御 (2017)
  • Author(s): 山本達郎、中尾光善、斉藤典子.
  • Publisher: 医学書院
• [Book] 基礎分子生物学II : 遺伝子発現制御機構 (田村隆明・浦聖惠 編) クロマチンから核構造へ (2017)
  • Author(s): 山本達郎、中尾光善、斉藤典子
  • Publisher: 東京化学同人
• [Remarks] がん研究所
  • URL: https://www.jfcr.or.jp/laboratory/department/cancer_biology/index.html
• [Remarks] 熊本大学発生医学研究所
  • URL: http://www.imeg.kumamoto-u.ac.jp/
• [Patent(Industrial Property Rights)] グリセオリンＩの作用機序とその利用 (2018)
  • Inventor(s): 山本達郎、立和名博昭、斉藤典子、井出剛、落合孝次
  • Industrial Property Rights Holder: 公益財団法人がん研究会、大豆エナジー株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-192177
  • Filing Date: 2018