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综述：核小体液-液相分离中早期形核过程的分子结构

张蒙，薛涵，刘建方，任罡*
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2024年 第43卷 第1期:  1000-6281（2024）01-114-007     下载地址：

综述：核小体液-液相分离中早期形核过程的分子结构

张蒙，薛涵，刘建方，任罡*

（1.The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA94720, USA；2.Quantitative Biosciences (QB3), University of California, Berkeley, CA94720, USA）

摘 要  研究揭示，核小体阵列在体外具有液-液相分离（liquid–liquid phase separation, LLPS）的内在特性，被认为在体内引导染色质区域的结构变化。然而，对于形成的异质凝聚物在分子水平的结构研究，长期以来受到技术限制，从而阻碍了研究人员对核小体液-液相分离的深入理解。为了解决这一难题，张蒙等运用先进的冷冻电子断层扫描技术（Cryo-electron tomography, Cryo-ET）、结合单分子电子断层重构（individual-particle electron tomography, IPET）和基于深度学习的分割技术，确定了液-液相分离在不同阶段的凝聚物的分子组织结构。该研究揭示，核小体的液-液相分离过程涉及到两个主要步骤：首先，旋节分解形成不规则的凝聚物；然后，这些凝聚物经过一个不稳定的过渡阶段，转化为更紧凑的球状核，进一步通过聚集更多旋节材料或与其它球状凝聚物的融合，逐渐形成更大的球状聚集体。此外，连接组蛋白H1催化旋节向球状凝聚物转变的速率，比旋节分解速度快出十倍以上。因此，推测这种转变可能涉及到核小体疏水表面的暴露，进而改变了核小体之间的相互作用。这些发现为染色质从间期结构向中期结构转变提供了新的物理机制线索。

关键词  核小体；核小体阵列；液-液相分离；凝聚物；旋节分解；成核和生长；组蛋白H1；染色质；非平均的单分子结构测定；冷冻电子断层扫描；单分子结构重构法

中图分类号：Q518.2；O552.6；Q336    文献标识码：A     doi:10.3969/j.issn.1000-6281.2024.01.013

  

A review of molecular structural at the early stages of nucleosome phase separation

ZHANG Meng1，2, XUE Han2, LIU Jian-fang 2, REN Gang 2*

（1. The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA94720, USA;2.Quantitative Biosciences (QB3), University of California, Berkeley, CA94720, USA）

Abstract Nucleosome arrays exhibit the intrinsicfeatureof liquid-liquid phase separation (LLPS) in vitro, hypothesized to orchestrate structural transformations within chromatin regions in vivo. However, the comprehensive understanding of nucleosome LLPS is impeded due to the technological limitation that restrictsthe molecular-level structural investigation of formed heterogeneous condensates. To circumvent this issue, Zhang et. al utilized the state-of-the-art cryo-electron tomography (cryo-ET) in conjunction with Individual-particle electron tomography (IPET) and deep learning-enabled segmentation techniques. This approach facilitated the characterization of molecular assemblies of LLPS condensates at various stages. The study uncovered that the LLPS process for nucleosomes was primarily biphasic: initially, irregular condensates formed through spinodal decomposition andunderwentan unstable transitional phase. This phase gaverise to more compact spherical nuclei which, in turn, gradually evolved into larger spherical aggregates via the accretion of more spinodal materials or fusion with other spherical condensates. Additionally, it was found that the linker histone H1 catalyzed the transition rate from spinodal to spherical condensates, exceeding the spinodal decomposition rate by over tenfold. Consequently, this transition might implicate the exposure of the hydrophobic surfaces of nucleosomes, thus modifying the inter-nucleosome interactions. These novel findings shed light on the underlying physical mechanism for the transformation of chromatin from its interphase structure to metaphase configuration, thereby enriching our understanding of chromatin dynamics.

Keywords nucleosome；nucleosome arrays；liquid-liquid phase separation；condensates；spinodal decomposition；nucleationand growth；histone H1；chromatin；single-molecule structure without averaging；Cryo-electron tomography；individual-particle electron tomography

 

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