| Project/Area Number |
21K06129
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 43050:Genome biology-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
SHARIF Jafar 国立研究開発法人理化学研究所, 生命医科学研究センター, 専任研究員 (00577968)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | Replication timing / SINE / H2Bub / CTCF / 3D genome / Epigenome / Euchromatin / Heterochromatin / A/B compartments / Transcription / DNA replication / H2B monoubiquitination / RNF20 / Retrotransposon |
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| Outline of Research at the Start |
本研究では、哺乳類細胞における複製タイミング（RT）の分子メカニズムを解析する。RTの決定に、ゲノムDNA配列そのものが貢献し、さらにそれらの配列を読み取るエピゲノム修飾因子が寄与しているとの仮説を立てる。我々の予備実験から、RNA polymerase II (POL2)による転写伸長反応がRTの制御に重要な役割を持ち、さらにPOL2の下流に集積するH2Bモノユビキチン化（H2Bub）がDNA複製の決定に関与している可能性が示唆された。本研究では、ゲノムのDNA配列がPOL2やH2Bubを誘導することにより、どのようにしてRTの決定に貢献するのか、その分子機構に迫る。
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| Outline of Final Research Achievements |
The vertebrate genome is organized into transcriptionally active euchromatin and incative heterochromatin. During the S-phase, euchromatin replicates early and heterochromatin replicates late, and this phenomenon is known as replication timing. In this project, I sought to identify the genetic and epigenetic features that regulate replication timing. I found that SINE (short interspersed nuclear elements) retrotransposons that are enriched in euchromatin, play a role to regulate early replication timing. Mechanistically, SINEs promote the deposition of histone H2B monoubiquitination (H2Bub), a transcription-coupled epigenetic mark, in euchromatin. Furthermore, SINEs mediate a crosstalk between H2Bub and the chromatin insulator protein CTCF, and this crosstalk plays a role for regulation of early replication timing. Taken together, my research reveals a previously unknown mechanism mediated by SINEs and H2Bub for regulation of replication timing.
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| Academic Significance and Societal Importance of the Research Achievements |
Replication timing defects have been linked with increased DNA damage, chromosomal translocations, and inappropriate cellular differentiation. By understanding the molecular mechanisms that regulate replication timing, it might be possible to therapeutically address the above cellular defects.
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