Saunders Hayden S, Chio Un Seng, Moore Camille M, Ramani Vijay, Cheng Yifan, Narlikar Geeta J
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Sci Adv. 2025 Aug 15;11(33):eads4473. doi: 10.1126/sciadv.ads4473.
The essential architectural protein HMGB1 increases accessibility of nucleosomal DNA and counteracts the effects of linker histone H1. However, HMGB1 is less abundant than H1 and binds nucleosomes more weakly, raising the question of how it competes with H1. Here, we find that HMGB1 increases nucleosomal DNA accessibility without displacing H1. HMGB1 also increases the dynamics of condensed, H1-bound chromatin. Unexpectedly, cryo-electron microscopy structures show HMGB1 bound at internal locations on nucleosomes and local DNA distortion. These sites are away from where H1 binds, explaining how HMGB1 and H1 can co-occupy a nucleosome. Our findings suggest a model where HMGB1 counteracts the effects of H1 by distorting nucleosomal DNA and disrupting interactions of the H1 carboxyl-terminal tail with DNA. Compared to mutually exclusive binding, co-occupancy by HMGB1 and H1 allows greater diversity in dynamic chromatin states. More generally, these results explain how architectural proteins acting at the nucleosome scale can have large effects on chromatin dynamics at the mesoscale.
关键的结构蛋白HMGB1可增加核小体DNA的可及性，并抵消连接组蛋白H1的作用。然而，HMGB1的丰度低于H1，且与核小体的结合较弱，这就引发了它如何与H1竞争的问题。在此，我们发现HMGB1增加了核小体DNA的可及性，而不会取代H1。HMGB1还增加了凝聚的、与H1结合的染色质的动力学。出乎意料的是，冷冻电子显微镜结构显示HMGB1结合在核小体内部位置并导致局部DNA扭曲。这些位点远离H1的结合位置，解释了HMGB1和H1如何能共同占据一个核小体。我们的研究结果提出了一个模型，即HMGB1通过扭曲核小体DNA并破坏H1羧基末端尾巴与DNA的相互作用来抵消H1的作用。与相互排斥的结合相比，HMGB1和H1的共同占据使得动态染色质状态具有更大的多样性。更普遍地说，这些结果解释了在核小体尺度上起作用的结构蛋白如何能对中尺度的染色质动力学产生重大影响。
