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Significance and mechanism of mutually exclusive inactive histone marks

Research Project

Project/Area Number 21H04764
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
Research InstitutionInstitute of Science Tokyo

Principal Investigator

木村 宏  東京工業大学, 科学技術創成研究院, 教授 (30241392)

Project Period (FY) 2021-04-05 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥41,730,000 (Direct Cost: ¥32,100,000、Indirect Cost: ¥9,630,000)
Fiscal Year 2024: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Fiscal Year 2023: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Fiscal Year 2022: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
Fiscal Year 2021: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Keywordsクロマチン / 遺伝子発現 / エピジェネティクス / ヒストン修飾 / 転写制御 / 染色体 / ヘテロクロマチン / エピジェネティクス制御 / 遺伝子発現制御
Outline of Research at the Start

遺伝子発現制御のメカニズムの解明は、生物学にとって最も重要な課題の一つである。転写の抑制にはヘテロクロマチンの形成が重要であるが、多細胞生物では「構成的ヘテロクロマチン」と「条件的ヘテロクロマチン」の2種類が存在する。これらの2種類のヘテロクロマチンはそれぞれに特徴的で排他的なヒストン修飾を持つが、この排他性の意義と形成メカニズムは謎のまま残されている。本研究では、誘導的エピジェネティック編集と生細胞イメージングを駆使して、ヒストン修飾の排他性の意義とメカニズムを明らかにする。これにより、多細胞生物の発生や分化の制御に重要な「条件的ヘテロクロマチン」形成機構を理解する。

Outline of Annual Research Achievements

H3K9me3とH3K27me3は共に転写抑制に関与する修飾であるが、排他的に存在し、それぞれ構成的ヘテロクロマチンと条件的ヘテロクロマチンの形成に働く。そこで、遺伝子発現の抑制に働くヘテロクロマチン構築機構の解明を目的として、H3K9me3とH3K27me3の排他性の生物学的意義と分子機構に関する解析を行った。
H3K27me3が濃縮する不活性X染色体をもつマウスMC12細胞を用いて、H3K27me3に結合する遺伝子コード型細胞内抗体(H3K27me3-mintbody)にH3K9のトリメチル化酵素であるSuv39H2の酵素活性ドメイン(SETドメイン)を融合したタンパク質(H3K27me3-mintbody-Suv39H2(SET))をドキシサイクリン(dox)依存的に発現させるための細胞株を樹立した。コントロールとして、メチル化酵素活性を持たないSETドメインの点変異体(H3K27me3-mintbody-Suv39H2(SET-Mut))を発現する細胞を樹立した。H3K27me3-mintbody-Suv39H2(SET)の発現誘導後1日で、H3K27me3が濃縮する不活性X染色体上へH3K9me3の局在が見られたが、SET-Mutではそのような濃縮は見られなかった。不活性X染色体上へのH3K9me3の濃縮は発現誘導後2-3日で最大に達した。この状態で、細胞は正常に増殖したが、不活性X染色体のDNA複製タイミングがより後期にシフトした。また、一過性の発現後にdoxを除去して発現を抑制したが、H3K9me3とH3K27me3の共局在状態は数日間維持された。これらの結果から、H3K9me3とH3K27me3の共局在は細胞にとって致死的ではないと考えられる。共局在がどの程度起こっているのかについて、今後調べていく必要がある。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

H3K9me3とH3K27me3を共局在させる系を樹立できた。今後この系を用いて解析が進むと考えられる。

Strategy for Future Research Activity

H3K27me3-mintbody-Suv39H2(SET)の発現により、H3K27me3が濃縮するクロマチンにH3K9me3がどの程度導入できたかについて、クロマチン免疫沈降により確認する。また、H3K9me3の導入効率を高めるために、SunTagなどを用いた増幅システムの使用を検討する。
一過性にH3K9me3とH3K27me3を共存させた後の変化について、時間経過を追って変動を解析する。その際、それぞれの脱メチル化酵素やメチル化酵素の局在性についても解析し、共局在から排他性に至る分子機構を明らかにする。

Report

(4 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Comments on the Screening Results   Annual Research Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (5 results) Journal Article (16 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 14 results,  Open Access: 14 results) Presentation (9 results) (of which Int'l Joint Research: 5 results,  Invited: 7 results) Remarks (6 results)

  • [Int'l Joint Research] Hubrecht Institute(オランダ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Memorial Sloan Kettering Cencer Center/Colorado State University(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Lausanne University(スイス)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Hubrecht Institute(オランダ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Memorial Sloan Kettering Cencer Center/Colorado State University(米国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Mutation of the SWI/SNF complex component Smarce1 decreases nucleosome stability in embryonic stem cells and impairs differentiation2024

    • Author(s)
      Kashiwagi Katsunobu、Yoshida Junko、Kimura Hiroshi、Shinjo Keiko、Kondo Yutaka、Horie Kyoji
    • Journal Title

      Journal of Cell Science

      Volume: 137 Issue: 6

    • DOI

      10.1242/jcs.260467

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Delayed localization of A-type lamins to the rupture sites in Hutchinson-Gilford progeria syndrome2023

    • Author(s)
      Kono Yohei、Pack Chan-Gi、Ichikawa Takehiko、Komatsubara Arata、Adam Stephen A.、Miyazawa Keisuke、Rolas Loic、Nourshargh Sussan、Medalia Ohad、Goldman Robert D.、Fukuma Takeshi、Kimura Hiroshi、Shimi Takeshi
    • Journal Title

      bioRxiv

      Volume: N/A

    • DOI

      10.1101/2023.09.02.555826

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epigenetic plasticity safeguards heterochromatin configuration in mammals2023

    • Author(s)
      Fukuda Kei、Shimi Takeshi、Shimura Chikako、Ono Takao、Suzuki Takehiro、Onoue Kenta、Okayama Satoko、Miura Hisashi、Hiratani Ichiro、Ikeda Kazuho、Okada Yasushi、Dohmae Naoshi、Yonemura Shigenobu、Inoue Azusa、Kimura Hiroshi、Shinkai Yoichi
    • Journal Title

      Nucleic Acids Research

      Volume: - Issue: 12 Pages: 6190-6207

    • DOI

      10.1093/nar/gkad387

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Organization of transcription and 3D genome as revealed by live-cell imaging2023

    • Author(s)
      Ochiai Hiroshi、Ohishi Hiroaki、Sato Yuko、Kimura Hiroshi
    • Journal Title

      Current Opinion in Structural Biology

      Volume: 81 Pages: 102615-102615

    • DOI

      10.1016/j.sbi.2023.102615

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Actin filaments accumulated in the nucleus and remain in the vicinity of condensing chromosomes during prophase in zebrafish early embryo2023

    • Author(s)
      Oda Haruka、Sato Yuko、Kawashima Shigehiro A.、Fujiwara Yusuke、Palfy Mate、Wu Edlyn、Vastenhouw Nadine L.、Kanai Motomu、Kimura Hiroshi
    • Journal Title

      Biology Open

      Volume: 12 Issue: 5

    • DOI

      10.1242/bio.059783

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Live-cell tracking of γ-H2AX kinetics reveals the distinct modes of ATM and DNA-PK in the immediate response to DNA damage2023

    • Author(s)
      Trakarnphornsombat Watanya、Kimura Hiroshi
    • Journal Title

      Journal of Cell Science

      Volume: 136 Issue: 8

    • DOI

      10.1242/jcs.260698

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The role of H3K9me3 in oral squamous cell carcinoma2023

    • Author(s)
      Tanaka Misako、Harada Hiroyuki、Kimura Hiroshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 640 Pages: 56-63

    • DOI

      10.1016/j.bbrc.2022.11.102

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] STREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity2022

    • Author(s)
      Ohishi Hiroaki、Shimada Seiru、Uchino Satoshi、Li Jieru、Sato Yuko、Shintani Manabu、Owada Hitoshi、Ohkawa Yasuyuki、Pertsinidis Alexandros、Yamamoto Takashi、Kimura Hiroshi、Ochiai Hiroshi
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 7672-7672

    • DOI

      10.1038/s41467-022-35286-2

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Single-cell profiling of transcriptome and histone modifications with EpiDamID2022

    • Author(s)
      Rang Franka J.、de Luca Kim L.、de Vries Sandra S.、Valdes-Quezada Christian、Boele Ellen、Nguyen Phong D.、Guerreiro Isabel、Sato Yuko、Kimura Hiroshi、Bakkers Jeroen、Kind Jop
    • Journal Title

      Molecular Cell

      Volume: 82 Issue: 10 Pages: 1956-1970.e14

    • DOI

      10.1016/j.molcel.2022.03.009

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Imaging transcription elongation dynamics by new technologies unveils the organization of initiation and elongation in transcription factories2022

    • Author(s)
      Kimura Hiroshi、Sato Yuko
    • Journal Title

      Current Opinion in Cell Biology

      Volume: 74 Pages: 71-79

    • DOI

      10.1016/j.ceb.2022.01.002

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nucleoplasmic lamin C rapidly accumulates at sites of nuclear envelope rupture with BAF and cGAS2022

    • Author(s)
      Kono Yohei、Adam Stephen A.、Sato Yuko、Reddy Karen L.、Zheng Yixian、Medalia Ohad、Goldman Robert D.、Kimura Hiroshi、Shimi Takeshi
    • Journal Title

      Journal of Cell Biology

      Volume: 221 Issue: 12

    • DOI

      10.1083/jcb.202201024

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Live imaging of transcription sites using an elongating RNA polymerase II-specific probe.2022

    • Author(s)
      Uchino S, Ito Y, Sato Y, Handa T, Ohkawa Y, Tokunaga M, Kimura H.
    • Journal Title

      J Cell Biol.

      Volume: 221 Issue: 2 Pages: 1-23

    • DOI

      10.1083/jcb.202104134

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] クロマチンの高次構造と転写制御2022

    • Author(s)
      後藤尚紀、木村 宏
    • Journal Title

      遺伝子医学

      Volume: 12 Pages: 135-140

    • NAID

      40022822913

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Visualizing looping of two endogenous genomic loci using synthetic zinc‐finger proteins with anti‐FLAG and anti‐HA frankenbodies in living cells2021

    • Author(s)
      Liu Yang、Zhao Ning、Kanemaki Masato T.、Yamamoto Yotaro、Sadamura Yoshifusa、Ito Yuma、Tokunaga Makio、Stasevich Timothy J.、Kimura Hiroshi
    • Journal Title

      Genes to Cells

      Volume: 26 Issue: 11 Pages: 905-926

    • DOI

      10.1111/gtc.12893

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Live-cell imaging probes to track chromatin modification dynamics2021

    • Author(s)
      Sato Yuko、Nakao Masaru、Kimura Hiroshi
    • Journal Title

      Microscopy

      Volume: 70 Issue: 5 Pages: 415-422

    • DOI

      10.1093/jmicro/dfab030

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ヒストン修飾2021

    • Author(s)
      田中美佐子、木村 宏
    • Journal Title

      遺伝子医学MOOK

      Volume: 36 Pages: 27-30

    • Related Report
      2021 Annual Research Report
  • [Presentation] ヘテロクロマチンにおけるヒストン修飾の排他性2024

    • Author(s)
      佐々木誓華、佐藤優子、木村宏
    • Organizer
      第41回染色体ワークショップ・第22回核ダイナミクス研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] クロマチン修飾と転写の生細胞ダイナミクス2023

    • Author(s)
      木村 宏
    • Organizer
      第4回ゲノム生物物理学セミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Dynamics of chromatin organization and transcription in early zebrafish embryos2023

    • Author(s)
      Hiroshi Kimura
    • Organizer
      RIKEN BDR Symposium 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamics of histone RNA polymerase II modifications in living cells2022

    • Author(s)
      Hiroshi Kimura
    • Organizer
      EMBO Workshop “Nuclear structure and dynamics”
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamics of histone and RNA polymerase II modifications in living cells2022

    • Author(s)
      Hiroshi Kimura
    • Organizer
      Japan-UK Regulation through Chromatin Conference 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Histone modification dynamics during transcription activation in living cells and embryos2022

    • Author(s)
      Hiroshi Kimura
    • Organizer
      Gordon Research Conference “Chromatin Structure and Function: Chromatin Modifications, RNA and Metabolism”
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Chromatin domain organization and dynamics in zebrafish embryos as revealed by live-cell imaging2022

    • Author(s)
      Hiroshi Kimura
    • Organizer
      EMBO Workshop “Awakening of the genome: The maternal-to-zygotic transition”
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 生細胞プローブを用いた不活性化X染色体動態と転写制御の解析2021

    • Author(s)
      20.佐藤優子, 内野哲志, 伊藤由馬, 前原一満, 大川恭行, 徳永万喜洋, 木村宏
    • Organizer
      日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Gene regulation and chromatin dynamics in living cells2021

    • Author(s)
      Hiroshi Kimura
    • Organizer
      The 79th of Annual Meeting of the Japanese Cancer Association
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Remarks] 東京工業大学・科学技術創成研究院・細胞制御工学研究センター・木村研究室

    • URL

      http://www.rcb.iir.titech.ac.jp/lab/kimura.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 東工大 木村研究室

    • URL

      http://kimura-lab.bio.titech.ac.jp/

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
  • [Remarks] 東工大 細胞制御工学研究センター

    • URL

      http://www.rcb.iir.titech.ac.jp/index.html

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
  • [Remarks] 東工大 リサーチデポジトリ T2R2

    • URL

      https://t2r2.star.titech.ac.jp/cgi-bin/researcherinfo.cgi?q_researcher_content_number=CTT100673940

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
  • [Remarks] リサーチマップ 木村宏

    • URL

      https://researchmap.jp/hiroshikimura

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
  • [Remarks] ORCID Hiroshi Kimura

    • URL

      https://orcid.org/0000-0003-0854-083X

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report

URL: 

Published: 2021-04-28   Modified: 2024-12-25  

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