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Analyzing Genomic Binding of Pyrrole-Imidazole Polyamides by Machine Learning

Research Project

Project/Area Number 17K15047
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Medical genome science
Research InstitutionChiba Cancer Center (Research Institute)

Principal Investigator

Lin Jason  千葉県がんセンター(研究所), がん治療開発グループ がん遺伝創薬研究室, 研究員 (80774124)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsケミカルバイオロジー / バイオインフォマティクス / ゲノミクス / エピゲノミクス / ゲノミックス / 総合生物 / ゲノム科学 / ゲノム医科学 / ゲノム創薬
Outline of Final Research Achievements

The high sequence specificity of minor groove-binding N-methylpyrrole-N-methylimidazole polyamides have made significant advances in cancer and disease biology, yet there have been few comprehensive reports on their off-target effects, most likely as a consequence of the lack of available tools in evaluating genomic binding, an essential aspect that has gone seriously underexplored. Compared to other N-heterocycles, the off-target effects of these polyamides and their specificity for the DNA minor groove and primary base pair recognition require the development of new analytical methods, which are missing in the field today. This project seeks to incorporate methods in computational biology and machine learning in the analysis of next-generation sequencing and expression profiling data to decipher off-target effects of these polyamides.

Academic Significance and Societal Importance of the Research Achievements

がん治療では、標的タンパク質構造によって、大半のがん標的に直接阻害することが難しい。ピロールイミダゾールポリアミド(PIP)は、DNA塩基認識によってDNA副溝結合を経由し、様々な癌遺伝子を阻害することが確認された。塩基認識では数学的なリミットがあり、ゲノム内には多くの結合配列が存在する。臨床実用へのため、PIPの治療効果、毒性や副作用などの安全性を予測しなければならない。本研究では、人工知能における機械学習法により、がんゲノムデータを解析し、PIPにおけるがんゲノムとの結合の評価及び臨床的な副作用の予測モデルを行った。本研究の結果によりPIPががん治療薬剤として実現することを期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (22 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (11 results) (of which Int'l Joint Research: 6 results) Remarks (4 results)

  • [Int'l Joint Research] 台湾・国立成功大学医療情報学研究所/台湾・国立成功大学電気電子工学大学院情報工学部(その他の国・地域)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] 台湾・国立成功大学医療情報学研究所/台湾・国立成功大学電気電子工学大学院情報工学部(その他の国・地域)

    • Related Report
      2018 Research-status Report
  • [Journal Article] The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding2020

    • Author(s)
      Lin Jason、Nagase Hiroki
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 4 Pages: 544-544

    • DOI

      10.3390/biom10040544

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CRED: a rapid peak caller for Chem-seq data2019

    • Author(s)
      Lin Jason、Kuo Tony、Horton Paul、Nagase Hiroki
    • Journal Title

      Journal of Open Source Software

      Volume: 4 Issue: 37 Pages: 1423-1423

    • DOI

      10.21105/joss.01423

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach.2019

    • Author(s)
      Lin J, Krishnamurthy S, Yoda H, Shinozaki Y, Watanabe T, Koshikawa N, Takatori A, Horton P and Nagase H.
    • Journal Title

      PLoS One.

      Volume: 14 Issue: 4 Pages: 4-4

    • DOI

      10.1371/journal.pone.0215247

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct Targeting of MYCN Gene Amplification by Site-Specific DNA Alkylation in Neuroblastoma2018

    • Author(s)
      Yoda Hiroyuki、Inoue Takahiro、Shinozaki Yoshinao、Lin Jason、Watanabe Takayoshi、Koshikawa Nobuko、Takatori Atsushi、Nagase Hiroki
    • Journal Title

      Cancer Research

      Volume: 79 Issue: 4 Pages: 830-840

    • DOI

      10.1158/0008-5472.can-18-1198

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hydrophobic structure of hairpin ten-ring pyrrole-imidazole polyamides enhances tumor tissue accumulation/retention in vivo2018

    • Author(s)
      Inoue Takahiro、Shimozato Osamu、Matsuo Nina、Mori Yusuke、Shinozaki Yoshinao、Lin Jason、Watanabe Takayoshi、Takatori Atsushi、Koshikawa Nobuko、Ozaki Toshinori、Nagase Hiroki
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 26 Issue: 9 Pages: 2337-2344

    • DOI

      10.1016/j.bmc.2018.03.029

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 塩基配列選択的な新規エピゲノム制御分子PIP-SAHAにおける機械学習法による遺伝子発現量影響の予測2020

    • Author(s)
      リン・ジェイソン、渡部隆義、杉山弘、永瀬浩喜
    • Organizer
      第5回AMEDがん若手研究者ワークショップ
    • Related Report
      2019 Annual Research Report
  • [Presentation] 発現プロファイリングによるDNA副溝結合剤のピロールイミダゾールポリアミドでの オフターゲット及び副作用の評価・予測2019

    • Author(s)
      Jason Lin, Sakthisri Krishnamurthy, Hiroyuki Yoda, Yoshinao Shinozaki, Takayoshi Watanabe, Nobuko Koshikawa, Atsushi Takatori, Paul Horton, Hiroki Nagase
    • Organizer
      第78回日本癌学会学術集会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Estimation of Phenotypes and Side Effects from DNA Minor-Groove-Binding Pyrrole-Imidazole Polyamides2019

    • Author(s)
      Jason Lin, Atsushi Takatori, Hiroki Nagase, Paul Horton
    • Organizer
      27th Conference on Intelligent Systems for Molecular Biology and the 18th European Conference on Computational Biology (ISMB/ECCB 2019)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ピロールイミダゾールポリアミドでの非特異的なゲノム結合および副作用の予測2019

    • Author(s)
      リン・ジェイソン、クリシュナムーティ・サクテイシリ、養田裕行、篠崎喜脩、渡部隆義、越川信子、高取敦志、ホートン・ポール、永瀬浩喜
    • Organizer
      第28回日本癌病態治療研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 臨床検体を用いた網羅的遺伝子発現解析によるがん増悪化分子フロントに関連するバイオマーカーの開発研究2019

    • Author(s)
      Lin Jason, 奥村和弘, 寺島裕也, 遠田悦子, 板倉明司, 松島綱治, 永瀬浩喜
    • Organizer
      AMEDがん若手研究者ワークショップ
    • Related Report
      2018 Research-status Report
  • [Presentation] Chem-seq: Evaluation of Genomewide Binding Effects of DNA Minor Groove-Binding Pyrrole Imidazole Polyamides2018

    • Author(s)
      Lin Jason, Takatori Atsushi, Horton Paul, Nagase Hiroki
    • Organizer
      RECOMB/ISCB Conference on Regulatory & Systems Genomics with DREAM Challenges
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ピロールイミダゾールポリアミドによるがん治療の評価:Chem-seq2018

    • Author(s)
      Lin Jason, 平岡桐子, Krishnamurthy Sakthisri, 井上貴博, 養田裕行, 篠崎喜脩, 渡部隆義, 高取敦志, 越川信子, 永瀬浩喜
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ゲノム解析によるピロールイミダゾールポリアミドで生化学的機能および臨床的副作用の予測2018

    • Author(s)
      Lin Jason, 平岡桐子, 養田裕行, Krishnamurthy Sakthisri, 篠崎喜脩, 渡部隆義, 高取敦志, 越川信子, Horton Paul, 永瀬浩喜
    • Organizer
      第27回日本癌病態治療研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] Design of a next-generation affinity-enrichment Chem-seq sequencing procedure to assess the biochemistry of minor-groove-binding pyrrole-imidazole polyamides2017

    • Author(s)
      J. Lin, A. Tataktori, K. Hiraoka, H. Yoda, S. Krishnamurthy, T. Inoue, T. Watanabe, T. Kuo, Y. Shinozaki, N. Koshikawa, P. Horton, H. Nagase
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Assessing oncotherapeutic efficacy of minor-groove-binding pyrrole-imidazole polyamides by Chem-seq sequencing2017

    • Author(s)
      J. Lin, K. Hiraoka, H. Yoda, A. Takatori, T. Watanabe, T. Kuo, Y. Shinozaki, N. Koshikawa, P. Horton, H. Nagase
    • Organizer
      "第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 機械学習によるピロールイミダゾールポリアミドでのゲノム結合の解析2017

    • Author(s)
      Jason Lin
    • Organizer
      "文部科学省先端モデル動物支援プラットフォーム・若手支援技術講習会
    • Related Report
      2017 Research-status Report
  • [Remarks] Chem-seq Read Enrichment Discovery: CRED

    • URL

      https://github.com/jlincbio/cred

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
  • [Remarks] pipoft: R package for estimating PIP side effects

    • URL

      https://github.com/jlincbio/pipoft

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
  • [Remarks] kmeRs2: k-Mers Similarity Score Matrix

    • URL

      https://github.com/jlincbio/kmeRs2

    • Related Report
      2019 Annual Research Report
  • [Remarks] rfpipeak: Chem-seq peak calling by random forest

    • URL

      https://github.com/jlincbio/rfpipeak

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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