美国马萨诸塞州总医院Jeannie T. Lee与清华大学李丕龙共同合作，近期取得重要工作进展。他们研究提出了Xist扩散行为与受限扩散的生物物理学基础。相关研究成果2025年1月16日在线发表于《细胞》杂志上。

据介绍，Xist RNA在顺式方向上沿着染色体扩散，从而启动X染色体失活。

研究人员揭示了其顺式限制扩散的生物物理基础。Xist RNA与异质核糖核蛋白K（HNRNPK）共同驱动液-液相分离（LLPS），将染色体包裹其中。HNRNPK液滴牵拉Xist RNA并将其内化。一旦被内化，Xist RNA会诱导进一步的相转变，使HNRNPK液滴“软化”。在体外，Xist RNA改变了凝聚体的变形性、粘附性和润湿性。

其他与Xist相互作用的蛋白质也被内化并截留在液滴内，导致Xist及其蛋白伴侣在凝聚体内富集。研究人员将这种液-液相分离归因于，HNRNPK的RGG结构域和Xist的重复序列B（RepB）基序。对这些基序进行突变会导致Xist RNA扩散，破坏多梳蛋白的募集，并阻碍Xist迁移所需的染色体区室混合。

因此，研究人员假设HNRNPK凝聚体中的相转变，使Xist能够在局部富集沉默因子，并通过HNRNPK包裹的染色体内部通道进行扩散。

附：英文原文

Title: A biophysical basis for the spreading behavior and limited diffusion of Xist

Author: Mingrui Ding, Danni Wang, Hui Chen, Barry Kesner, Niklas-Benedikt Grimm, Uri Weissbein, Anna Lappala, Jiying Jiang, Carlos Rivera, Jizhong Lou, Pilong Li, Jeannie T. Lee

Issue&Volume: 2025-01-16

Abstract: Xist RNA initiates X inactivation as it spreads in cis across the chromosome. Here, we reveal a biophysical basis for its cis-limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome. HNRNPK droplets pull on Xist and internalize the RNA. Once internalized, Xist induces a further phase transition and “softens” the HNRNPK droplet. Xist alters the condensate’s deformability, adhesiveness, and wetting properties in vitro. Other Xist-interacting proteins are internalized and entrapped within the droplet, resulting in a concentration of Xist and protein partners within the condensate. We attribute LLPS to HNRNPK’s RGG and Xist’s repeat B (RepB) motifs. Mutating these motifs causes Xist diffusion, disrupts polycomb recruitment, and precludes the required mixing of chromosomal compartments for Xist’s migration. Thus, we hypothesize that phase transitions in HNRNPK condensates allow Xist to locally concentrate silencing factors and to spread through internal channels of the HNRNPK-encapsulated chromosome.

DOI: 10.1016/j.cell.2024.12.004

Source:https://www.cell.com/cell/abstract/S0092-8674(24)01417-X