Elucidation of ectopic formation of super enhancers by SATB1 for breast cancer malignancy

• Project/Area Number: 19K07664
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyushu University (2020-2021); Shiga University of Medical Science (2019)
• Principal Investigator: Tomimatsu Kosuke 九州大学, 生体防御医学研究所, 助教 (00614926)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: スーパーエンハンサー / 乳がん / SATB1 / がん / エピゲノム

Outline of Research at the Start

SATB1はゲノムのオーガナイザーと呼ばれ、核内におけるDNAの構造変化に寄与する。この遺伝子は悪性化した乳がん細胞で顕著に発現し、がんの転移に関連する遺伝子の発現を促している事が報告されている。これらの遺伝子座の幾つかはスーパーエンハンサー(SE)と呼ばれる高密度エンハンサーの集合体を形成し、強力な遺伝子発現誘導が起こっている事が予想されるが、本来形成されない部位でのSE形成機構は明らかになっていない。そこで本研究では悪性化した乳がん細胞に高発現するSATB1と、その異所的なSE形成との関連性を明らかにする。

Outline of Final Research Achievements

We aimed to determine the association of SATB1 with super-enhancers (SEs) formation around metastasis-related genes during the malignant transformation of breast cancer cells. Forced expression of SATB1 in non-invasive breast cancer cell line MCF-7 transiently indicated malignant phenotypes. It was difficult to use as the cancer progression model. Therefore, we used a lung cancer cell line A549, which can be stably induced epithelial-mesenchymal transition (EMT), to analyze time-dependent SE formation by BRD4 ChIP-Seq. The results indicated that SEs were reorganized during EMT. It was also shown that the motifs of transcription factors enriched in SEs were altered during EMT.

Academic Significance and Societal Importance of the Research Achievements

本研究では、がん細胞が転移能を獲得する過程で（EMT）、時間経過に伴いSEのゲノムワイドな分配パターンが変化することを示した。SEにエンリッチする転写因子のモチーフはEMTの時間経過に伴い変化することから、特定の転写因子の機能を阻害することでがん細胞の転移能獲得を遅延または阻害できる可能性が示された。マウスやIn vitro実験による検証は必要ではあるが、将来的ながんの治療標的となる可能性が示された。

Research Products

• [Journal Article] Locus-specific induction of gene expression from heterochromatin loci during cellular senescence (2022)
  • Author(s): Tomimatsu K, Bihary D, Olan I, Parry AJ, Schoenfelder S, Chan ASL, Slater GSC, Ito Y, Rugg-Gunn PJ, Kirschner K, Bermejo-Rodriguez C, Seko T, Kugoh H, Shiraishi K, Sayama K, Kimura H, Fraser P, Narita M, Samarajiwa SA, Narita M
  • Journal Title: Nature Aging Volume: 2 Issue: 1 Pages: 31-45
  • DOI: 10.1038/s43587-021-00147-y
  • Peer Reviewed
• [Journal Article] Unusual nucleosome formation and transcriptome influence by the histone H3mm18 variant (2021)
  • Author(s): Hirai Seiya、Tomimatsu Kosuke、Miyawaki-Kuwakado Atsuko、Takizawa Yoshimasa、Komatsu Tetsuro、Tachibana Taro、Fukushima Yutaro、Takeda Yasuko、Negishi Lumi、Kujirai Tomoya、Koyama Masako、Ohkawa Yasuyuki、Kurumizaka Hitoshi
  • Journal Title: Nucleic Acids Research Volume: 50 Issue: 1 Pages: 72-91
  • DOI: 10.1093/nar/gkab1137
  • Peer Reviewed / Open Access
• [Journal Article] Modeling population size independent tissue epigenomes by ChIL-seq with single thin sections. (2021)
  • Author(s): Maehara K, Tomimatsu K, Harada A, Tanaka K, Sato S, Fukuoka M, Okada S, Handa T, Kurumizaka H, Saitoh N, Kimura H, Ohkawa Y.
  • Journal Title: Mol Syst Biol. Volume: 17
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide analysis of chromatin structure changes upon MyoD binding in proliferative myoblasts during the cell cycle (2021)
  • Author(s): Wu Qianmei、Fujii Takeru、Harada Akihito、Tomimatsu Kosuke、Miyawaki-Kuwakado Atsuko、Fujita Masatoshi、Maehara Kazumitsu、Ohkawa Yasuyuki
  • Journal Title: The Journal of Biochemistry Volume: - Issue: 6 Pages: 653-661
  • DOI: 10.1093/jb/mvab001
  • NAID: 40022687719
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptome analysis of gene expression changes upon enzymatic dissociation in skeletal myoblasts. (2021)
  • Author(s): Miyawaki-Kuwakado A, Wu Q, Harada A, Tomimatsu K, Fujii T, Maehara K, Ohkawa Y.
  • Journal Title: Genes Cells. Volume: 26 Issue: 7 Pages: 530-540
  • DOI: 10.1111/gtc.12870
  • Peer Reviewed / Open Access
• [Journal Article] Long non-coding RNA MANCR is a target of BET bromodomain protein BRD4 and plays a critical role in cellular migration and invasion abilities of prostate cancer. (2020)
  • Author(s): Nagasawa M, Tomimatsu K, Terada K, Kondo K, Miyazaki K, Miyazaki M, Motooka D, Okuzaki D, Yoshida T, Kageyama S, Kawamoto H, Kawauchi A, Agata Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 526 Issue: 1 Pages: 128-134
  • DOI: 10.1016/j.bbrc.2020.03.043
  • NAID: 120006839258
  • Peer Reviewed
• [Presentation] 細胞老化における特異的ヘテロクロマチン領域からの遺伝子発現誘導 (2021)
  • Author(s): 富松航佑
  • Organizer: 第１４回日本エピジェネティクス研究会
• [Book] 遺伝子医学MOOK36 (2021)
  • Author(s): 富松航佑, 大川 恭行
  • Total Pages: 218
  • Publisher: 株式会社メディカルドゥ
  • ISBN: 9784909508119
• [Remarks] 九州大学 トランスクリプトミクス分野ホームページ
  • URL: https://tx.bioreg.kyushu-u.ac.jp/