分子动力学模拟揭示了H3K9和H3K27三甲基化对染色质成分的细微影响。

Molecular dynamics simulations reveal subtle consequences of H3K9 and H3K27 tri-methylation on chromatin constituents.

作者信息

Portillo-Ledesma Stephanie, Li Zilong, Schlick Tamar

机构信息

Department of Chemistry, New York University, New York, New York; Simons Center for Computational Physical Chemistry, New York University, New York, New York.

Department of Chemistry, New York University, New York, New York; Courant Institute of Mathematical Sciences, New York University, New York, New York; New York University-East China Normal University Center for Computational Chemistry, New York University Shanghai, Shanghai, China; Simons Center for Computational Physical Chemistry, New York University, New York, New York.

出版信息

Biophys J. 2025 Aug 6. doi: 10.1016/j.bpj.2025.08.002.

DOI:10.1016/j.bpj.2025.08.002

PMID:40776446

Abstract

Epigenetic modifications of histone tails are key mechanisms of genome regulation. In particular, tri-methylation of lysines (K) 9 and K27 of the histone H3 tail is important for genome silencing. In this work, we explore, using all-atom molecular dynamics simulations, the effect of these two epigenetic marks on the structure and interactions of the H3 tail in several contexts: isolated tails, nucleosomes, chromatosomes, and stacked nucleosomes. Overall, we find that although the isolated tails do not show significant conformational changes upon methylation, a more flexible and extended H3 tail compared to the native tail results in the nucleosome systems, with K9 methylation effects more pronounced. This change could facilitate the interaction of the tail with protein readers like heterochromatin protein 1 or Polycomb group. We also observe that both methylations increase the interactions of the H3 tail with the linker DNA in the context of the chromatosome, producing a chromatosome with tighter linker DNA, which could favor chromatin compaction. For stacked nucleosomes mimicking i±2 zigzag interactions, methylation of either K9 or K27 reduces the interactions of one of the H3 tails with its parental nucleosome and increases its interactions with the nonparental nucleosome, which could also help compact the chromatin fiber. In the three nucleosome-containing systems, we observe an asymmetry between the two tails, especially in the chromatosome, where one tail extends to interact with the linker DNA. This asymmetry modulates the effect that methylation has on each tail. Thus, overall, methylations of K9 and K27 have a subtle but notable impact on the H3 tail structure and its interactions within the chromatin fiber. These results help explain how this epigenetic modification compacts chromatin fibers and promotes longer-range interactions; these changes also guide how to approximate these effects in coarse-grained chromatin models.

摘要

组蛋白尾部的表观遗传修饰是基因组调控的关键机制。特别是，组蛋白H3尾部赖氨酸（K）9和K27的三甲基化对于基因组沉默很重要。在这项工作中，我们使用全原子分子动力学模拟，在几种情况下探索这两种表观遗传标记对H3尾部结构和相互作用的影响：分离的尾部、核小体、染色质小体和堆叠核小体。总体而言，我们发现虽然分离的尾部在甲基化后没有显示出明显的构象变化，但与天然尾部相比，核小体系统中的H3尾部更灵活且伸展，K9甲基化的影响更明显。这种变化可能促进尾部与异染色质蛋白1或多梳蛋白家族等蛋白质读取器的相互作用。我们还观察到，在染色质小体的背景下，两种甲基化都增加了H3尾部与连接DNA的相互作用，产生了一种连接DNA更紧密的染色质小体，这可能有利于染色质压缩。对于模拟i±2锯齿形相互作用的堆叠核小体，K9或K27的甲基化会减少其中一条H3尾部与其亲本核小体的相互作用，并增加其与非亲本核小体的相互作用，这也有助于压缩染色质纤维。在三个包含核小体的系统中，我们观察到两条尾部之间存在不对称性，特别是在染色质小体中，其中一条尾部延伸以与连接DNA相互作用。这种不对称性调节了甲基化对每条尾部的影响。因此，总体而言，K9和K27的甲基化对H3尾部结构及其在染色质纤维内的相互作用有微妙但显著的影响。这些结果有助于解释这种表观遗传修饰如何压缩染色质纤维并促进更远距离的相互作用；这些变化也指导了如何在粗粒度染色质模型中近似这些影响。