MCM复合体是限制凝聚因介导循环挤出的障碍物
Bart J H Dequeker1, Matthias J Scherr2, Hugo B Brandão3,4
1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
Nature
|May 18, 2022
概括
微染色体维护 (MCM) 复合体作为一个屏障,阻碍了DNA循环的凝聚. 这一发现揭示了MCM复合体如何影响三维基因组结构和姐妹染色体凝聚力.
科学领域:
- 基因组学
- 分子生物学
- 细胞生物学
背景情况:
- 细胞基因组组织成循环和拓关联域 (TAD),对基因调节和基因组稳定性至关重要.
- 已知凝聚素将DNA挤出成循环,通常在CTCF边界停止.
- 像MCM复合体这样的DNA绑定机器在阻碍循环挤出中的作用仍然很大程度上是未知的.
研究的目的:
- 调查DNA绑定机器,特别是微染色体维护 (MCM) 复合体,是否作为凝聚素介导循环挤出的障碍.
- 了解MCM复合体对CTCF固定环和TAD边界绝缘形成的影响.
- 阐明MCM复合体影响三维基因组组织和姐妹染色体凝聚力的机制.
主要方法:
- 单核Hi-C (高分辨率染色体构成捕获) 在小鼠生殖细胞和HCT116细胞中.
- 计算模拟以模拟MCM复杂行为作为障碍.
- 在体外观察单分子成像来观察MCM-凝聚素相互作用.
- 创建含有人类凝聚素相互作用图案的仿真酵母MCM.
主要成果:
- 在G1阶段,MCM复合加载减少了CTCF固的循环,并降低了TAD边界绝缘.
- 在体和体外,MCM充当限制凝聚蛋白转移的物理障碍.
- 具有特定动机的化学MCM诱导凝聚性暂停,表明MCM是活跃的障碍物.
- MCM 影响 HCT116 细胞中 CTCF 定环数和基因表达.
结论:
- 微染色体维护 (MCM) 复合体作为一个屏障,在CTCF部位前限制凝聚素介导循环挤出.
- MCM复合体被确定为影响姐妹染色体凝聚力的活性障碍物.
- 不同的循环挤出障碍,包括MCM复合体,在塑造三维基因组组织方面发挥着关键作用.
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