研究課題/領域番号 |
21K06129
|
研究種目 |
基盤研究(C)
|
配分区分 | 基金 |
応募区分 | 一般 |
審査区分 |
小区分43050:ゲノム生物学関連
|
研究機関 | 国立研究開発法人理化学研究所 |
研究代表者 |
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)
|
研究期間 (年度) |
2021-04-01 – 2024-03-31
|
研究課題ステータス |
交付 (2022年度)
|
配分額 *注記 |
4,160千円 (直接経費: 3,200千円、間接経費: 960千円)
2023年度: 780千円 (直接経費: 600千円、間接経費: 180千円)
2022年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
2021年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
|
キーワード | Euchromatin / Heterochromatin / Replication timing / A/B compartments / Transcription / Epigenome / DNA replication / H2B monoubiquitination / RNF20 / Retrotransposon |
研究開始時の研究の概要 |
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。
|
研究実績の概要 |
The eukaryotic genome is organized into eu- or hetero-chromatin domains, the former is gene-rich and transcriptionally active, while the latter is gene-poor and transcriptionally inactive. Eu- or hetero-chromatin are also analogous to A or B compartments, calculated from the PC1 (primary component 1) value of the eigenvector of the Hi-C (a method for chromatin conformation capture) matrix. During S phase, A compartments replicate early while B compartments replicate late. It is, however, not understood if A/B compartmentalization and early/late replication timing is mechanistically linked.
|
現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The aim of this project is to determine if A/B compartments and early/late replication timing are mechanistically linked. By taking advantage of degron-based acute depletion of transcriptional machinery, I have found that transcriptional elongation functions as a molecular link to connect A/B compartments and early/late replication timing. Furthermore, by taking advantage of a conditional gene knockout strategy, I have been able to identify an epigenetic mechanism that functions directly downstream of transcriptional elongation to connect compartmentalization with replication timing. Finally, via genomics-based screening and genetic knock-in experiments, I have determined specific genetic sequences that play a key role in connecting A/B compartments with early/late replication timing.
|
今後の研究の推進方策 |
My research reveals that in addition to regulating gene expression, transcription possesses distinct roles to regulate 3D genome and replication timing. Intriguingly, this role of transcription appears to be mediated by distinct epigenetic mechanisms that are deposited downstream of transcriptional elongation. In this project, I have focused on one such epigenetic mechanism that is enriched in A compartments and promotes early replication. By research, however, has unveiled several other epigenetic pathways that may also take part in regulation of the 3D genome and replication timing. Some of these epigenetic mechanisms are expected to be involved in regulation of B compartments and/or late replication timing. Further exploration of these mechanisms is my future goal.
|