替代mRNA剪接控制了基因组H3K27脱甲基酶UTX/KDM6A的功能
Omid Fotouhi1,2, Sheikh Nizamuddin1,2, Stephanie Falk3
1Department of Urology, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
Cancers
|June 28, 2023
概括
UTX/KDM6A的替代拼接产生了多种不同的mRNA变体. 这些变体控制UTX蛋白的局部化和染色体调节复合体内的相互作用,影响发育和癌症.
科学领域:
- 表观遗传学和基因调控
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- UTX / KDM6A 基因组脱甲基酶对发育至关重要,并且在尿路癌等癌症中经常发生突变.
- 以前对UTX蛋白质的研究基本上忽视了mRNA拼接变异的影响.
研究的目的:
- 在人类细胞系和膀癌组织中全面分析UTX/KDM6A拼接事件.
- 调查替代拼接如何影响UTX蛋白位址,染色质关联和复杂相互作用.
主要方法:
- 利用纳米孔测序进行UTX/KDM6A拼接的综合分析.
- 采用定量质谱法来识别蛋白质复杂相互作用.
- 在人类细胞系和膀癌组织样本中分析了拼接.
主要成果:
- 广泛的替代拼接发生在UTXmRNAs的中心区域 (12-17个外显子).
- 很大一部分UTXmRNA缺乏14号外因子,从而改变了核局部和染色体关联.
- 所有UTX异构体都集成到MLL3/MLL4,PR-DUB和MiDAC复合体中,其中一个新异构体显示了改变的相互作用.
结论:
- UTX/KDM6A mRNA经历了广泛的替代拼接,显著影响UTX蛋白功能.
- 剪接变体决定UTX亚细胞局部化及其与染色体调节机制的接触.
- 了解UTX拼接对于理解其在发育和癌症进展中的作用至关重要.
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