Mechanism of regulation of gene expression levels enabled by diversity in histone composition.

• Project/Area Number: 19H03158
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: Kyushu University
• Principal Investigator: Maehara Kazumitsu 九州大学, 生体防御医学研究所, 助教 (90726431)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: ヒストンバリアント / クロマチン / ホッジ分解 / エネルギー地形

Outline of Research at the Start

本研究では、ホッジ分解と呼ばれる数理的手法を応用した一細胞データに内在する「多層的な時間構造」を抽出する技術を開発する。これを独自に開発した少数細胞エピゲノムプロファイル法により取得した骨格筋の分化・再生過程の一細胞データに時間構造を与える。そして、データ駆動的にクロマチン構造変化のダイナミクスをエネルギー地形として再構築する。これらのアプローチにより、細胞分化におけるクロマチン構造変化を時空間的に理解することで、ヒストン組成の多様性が可能とする遺伝子発現量制御機構の解明を目指す。

Outline of Final Research Achievements

We established a genome-wide chromatin profiling technique for small tissue sections by optimizing ChIL technology to analyze the relationship between histone composition and differentiation process in muscle tissue in detail. We also developed a data analysis method to reconstruct energy landscapes from single cell data. We further developed the ChIL method and extended it to a method using two antibodies simultaneously. We are attempting to apply this method to the extraction of chromatin dynamics during differentiation by looking at the two different molecules in the same cell. The analyses of novel histone variants were published mainly through collaborative research.

Academic Significance and Societal Importance of the Research Achievements

細胞分化におけるクロマチン構造変化を時空間的に解析する技術を確立することで、ヒストン組成の多様性が可能とする遺伝子発現量制御機構の解明が期待できる。データ駆動的なダイナミクス抽出は、他分野のデータ解析に応用可能である。また、単一細胞遺伝子発現データを対象とする新規細胞プロファイリング法は、従来の個別かつ大量の遺伝子の統計的検定では見えなかった複数遺伝子間の依存関係を含む新しい遺伝子機能の発見が期待できる。

Research Products

• [Journal Article] Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load. (2021)
  • Author(s): Kaneshige A, Kaji T, Zhang L, Saito H, Nakamura A, Kurosawa T, Ikemoto-Uezumi M, Tsujikawa K, Seno S, Hori M, Saito Y, Matozaki T, Maehara K, Ohkawa Y, Potente M, Watanabe S, Braun T, Uezumi A, Fukada SI.
  • Journal Title: Cell Stem Cell. Volume: 29 Issue: 2 Pages: 265-280
  • DOI: 10.1016/j.stem.2021.11.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Discriminative feature of cells characterizes cell populations of interest by a small subset of genes. (2021)
  • Author(s): Fujii T, Maehara K, Fujita M, Ohkawa Y.
  • Journal Title: PLoS Comput Biol. Volume: 17 Issue: 11 Pages: e1009579-e1009579
  • DOI: 10.1371/journal.pcbi.1009579
  • 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] An extensive and dynamic trans-omic network illustrating prominent regulatory mechanisms in response to insulin in the liver. (2021)
  • Author(s): Matsuzaki F, Uda S, Yamauchi Y, Matsumoto M, Soga T, Maehara K, Ohkawa Y, Nakayama KI, Kuroda S, Kubota H.
  • Journal Title: Cell Rep. Volume: 36 Pages: 109569-109569
  • Peer Reviewed / Open Access
• [Journal Article] High-depth spatial transcriptome analysis by photo-isolation chemistry. (2021)
  • Author(s): Honda M, Oki S, Kimura R, Harada A, Maehara K, Tanaka K, Meno C, Ohkawa Y.
  • Journal Title: Nat Commun. Volume: 12 Issue: 1 Pages: 4416-4416
  • DOI: 10.1038/s41467-021-24691-8
  • NAID: 120007141968
  • 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] Chromatin structure-dependent histone incorporation revealed by a genome-wide deposition assay (2021)
  • Author(s): Hiroaki Tachiwana, Mariko Dacher, Kazumitsu Maehara, Akihito Harada, Yosuke Seto, Ryohei Katayama, Yasuyuki Ohkawa, Hiroshi Kimura, Hitoshi Kurumizaka, Noriko Saitoh
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.66290
  • 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] H4K20me1 and H3K27me3 are concurrently loaded onto the inactive X chromosome but dispensable for inducing gene silencing (2021)
  • Author(s): Tjalsma Sjoerd J D、Hori Mayako、Sato Yuko、Bousard Aurelie、Ohi Akito、Raposo Ana Claudia、Roensch Julia、Le Saux Agnes、Nogami Jumpei、Maehara Kazumitsu、Kujirai Tomoya、Handa Tetsuya、Bages‐Arnal Sandra、Ohkawa Yasuyuki、Kurumizaka Hitoshi、da Rocha Simao Teixeira、Zylicz Jan J、Kimura Hiroshi、Heard Edith
  • Journal Title: EMBO reports Volume: 22 Issue: 3
  • DOI: 10.15252/embr.202051989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chromatin integration labeling for mapping DNA-binding proteins and modifications with low input. (2020)
  • Author(s): Tetsuya Handa, Akihito Harada, Kazumitsu Maehara, Shoko Sato, Masaru Nakao, Naoki Goto, Hitoshi Kurumizaka, Yasuyuki Ohkawa, Hiroshi Kimura.
  • Journal Title: Nat Protoc. Volume: 15 Issue: 10 Pages: 3334-3360
  • DOI: 10.1038/s41596-020-0375-8
  • Peer Reviewed / Open Access
• [Journal Article] Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. (2019)
  • Author(s): Oka M, Mura S, Otani M, Miyamoto Y, Nogami J, Maehara K, Harada A, Tachibana T, Yoneda Y, Ohkawa Y
  • Journal Title: Elife Volume: 8
  • DOI: 10.7554/elife.46667
  • Peer Reviewed / Open Access
• [Journal Article] Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle. (2019)
  • Author(s): Fukuda S, Kaneshige A, Kaji T, Noguchi YT, Takemoto Y, Zhang L, Tsujikawa K, Kokubo H, Uezumi A, Maehara K, Harada A, Ohkawa Y, Fukada SI.
  • Journal Title: eLife Volume: 8
  • DOI: 10.7554/elife.48284
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis. (2019)
  • Author(s): †Abdalla MOA, †Yamamoto T, Maehara K, Ohkawa Y, Miura H, Hiratani I, Nakayama H, Nakao M, *Saitoh N
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 3778-3778
  • DOI: 10.1038/s41467-019-11378-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biochemical analysis of nucleosome targeting by Tn5 transposase (2019)
  • Author(s): Sato S, Arimura Y, Kujirai T, Harada A, Maehara K, Nogami J, Ohkawa Y, Kurumizaka H.
  • Journal Title: Open Biol. Volume: 9 Issue: 8 Pages: 190116-190116
  • DOI: 10.1098/rsob.190116
  • Peer Reviewed / Open Access
• [Journal Article] Dmrt factors determine the positional information of cerebral cortical progenitors via differential suppression of homeobox genes. (2019)
  • Author(s): Konno D, Kishida C, Maehara K, Ohkawa Y, Kiyonari H, Okada S, Matsuzaki F
  • Journal Title: Development Volume: 146 Issue: 15 Pages: 174243-174243
  • DOI: 10.1242/dev.174243
  • Peer Reviewed / Open Access
• [Journal Article] Calcineurin Broadly Regulates the Initiation of Skeletal Muscle-Specific Gene Expression by Binding Target Promoters and Facilitating the Interaction of the SWI/SNF Chromatin Remodeling Enzyme. (2019)
  • Author(s): Witwicka H, Nogami J, Syed SA, Maehara K, Padilla-Benavides T, Ohkawa Y, Imbalzano AN
  • Journal Title: Mol Cell Biol. Volume: 39 Issue: 19
  • DOI: 10.1128/mcb.00063-19
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 単一細胞オミクスデータの性能評価から利活用まで (2022)
  • Author(s): 前原一満
  • Organizer: マルチNGSオミクス解析研究会
  • Invited
• [Presentation] 筋組織維持システムの理解に向けたオミクスデータ解析技術の開発 (2021)
  • Author(s): 前原一満、原田哲仁、藤井健、大川恭行
  • Organizer: 第44回日本分子生物学会
  • Invited
• [Presentation] 生命現象を理解するためのオミクスデータ解析技法 (2020)
  • Author(s): 前原一満
  • Organizer: バイオ統計セミナー
  • Invited
• [Presentation] Towards extracting chromatin dynamics from single-cell measurements. (2019)
  • Author(s): Kazumitsu Maehara, Yasuyuki Ohkawa
  • Organizer: 第47回日本分子生物学会年会
  • Invited
• [Presentation] Modeling latent flows in single cell data. (2019)
  • Author(s): Kazumitsu Maehara
  • Organizer: EMBO Symposia:Multi-Omics
  • Int'l Joint Research
• [Presentation] 一細胞データから細胞分化の流れをモデル化する試み (2019)
  • Author(s): 前原一満
  • Organizer: 新学術領域研究「数理シグナル」若手ワークショップ
• [Presentation] クロマチン挿入標識（ChIL）法による空間エピゲノム解析 (2019)
  • Author(s): 前原一満
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
• [Book] 1細胞エピゲノム解析技術開発の最前線 (2021)
  • Author(s): 大川 恭行,原田 哲仁,前原 一満
  • Total Pages: 6
  • Publisher: 医歯薬出版株式会社 週刊医学のあゆみ
• [Book] 実験医学増刊 Vol.38 No.20 機械学習を生命科学に使う！「scRNA-seqを用いた細胞系譜の軌跡推定-データの背後の流れを読み取る技術-」 (2020)
  • Author(s): 前原一満, 大川恭行
  • Total Pages: 8
  • Publisher: 羊土社
  • ISBN: 9784758103916
• [Book] 実験医学別冊 エピゲノムをもっと見るためのクロマチン解析実践プロトコール「少数細胞クロマチン解析法の性能を比較する」 (2020)
  • Author(s): 前原一満
  • Total Pages: 4
  • Publisher: 羊土社
  • ISBN: 9784758122481
• [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/
• [Remarks] 単一細胞データ解析ソフトウェア - ddhodge
  • URL: https://github.com/kazumits/ddhodge