m6Aは,堅固なドロソフィラの性別決定のためのSxl代替プレ-mRNAスプライシングを強化する
Irmgard U Haussmann1,2, Zsuzsanna Bodi3, Eugenio Sanchez-Moran1
1School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Nature
|December 6, 2016
まとめ
N-メチラデノシン (m6A) RNAの改変は,ドロソフィラのSex lethal (Sxl) 遺伝子の女性特有の代替スプライシングに不可欠である. この古代のメカニズムは,m6Aリーダーのタンパク質YT521-Bを巻き込み,遺伝子発現を調節し,女性では投与量の補償を防ぐ.
科学分野:
- 分子生物学
- エピジェネティクス
- RNA 生物学
背景:
- N-メチラデノシン (m6A) は,YTHドメインタンパク質によって認識される,真核伝達 RNA (mRNA) の最も一般的な内部変異である.
- METTL3とWTAPを含むm6Aメチロソーム複合体は,DrosophilaのIme4やFl(2) dのような同種で保存されている.
- 内部領域におけるm6Aの役割と,特に性決定における代替スプライシングの制御におけるその正確な機能は,ほとんど知られていなかった.
研究 の 目的:
- ドロソフィラのm6Aの機能,特に代替スプライシングと性決定におけるその役割を調査する.
- m6AがSex lethal (Sxl) 遺伝子のスプライシングに影響を与えるメカニズムを解明する.
- Sxl前mRNAにおけるm6A信号を解読するm6Aリーダーのタンパク質を識別する.
主な方法:
- ドロソフィラ・イメ4型変異体の生成と分析
- 性別決定アッセイと変異体の現象分析
- RNAシーケンシングと代替スプライシング分析
- m6Aリーダーのタンパク質YT521-Bの機能の調査.
主要な成果:
- Ime4 (Ime4-null変異体) を欠いたドロソフィラは生存可能だが,男性偏りの性決定を示し,飛べない.
- m6Aは,Sxlの女性特異的な代替スプライシングに不可欠であり,女性の発達に不可欠です.
- m6Aはまた,女性における男性特異的なレタル2 (msl-2) を翻訳的に抑制し,用量補償を防ぐ.
- m6Aリーダーのタンパク質YT521-Bは,Sxlイントロンのm6Aに直接結合し,その欠如はIme4変異体をフェノコピーする.
- m6Aの喪失は他の遺伝子,特に5' UTRの代替スプライシングに影響し,全般的に代謝遺伝子発現に影響します.
結論:
- m6Aの修正は,雌性特異性Sxlの代替スプライシングとドロソフィラの性別決定に不可欠である.
- m6AリーダプロテインYT521-Bは,m6A依存型スプライシングの調節に重要な役割を果たします.
- この研究は,特に性決定の文脈で,代替スプライシングを通じて遺伝子発現を調節する古くからある特定のメカニズムとしてm6Aを明らかにしています.
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