Histone variants regulate replication, transcription, DNA damage repair, and chromosome segregation. Though widely accepted as a paradigm, it has not been rigorously demonstrated that histone variants encode unique mechanical properties. Here, we present a new theoretical approach called minimal cylinder analysis that uses strain fluctuations to determine the Young's modulus of nucleosomes from all-atom molecular dynamics simulations. Recently, we validated this computational tool against in vitro single-molecule nanoindentation of histone variant nucleosomes. In this report, we further extend minimal cylinder analysis to study the biophysical properties of hybrid nucleosomes that are known to exist in human cancer cells and contain H3 histone variants CENP-A and H3.3. Here, we report that the heterotypic nucleosome has an intermediate elasticity (8.5 ± 0.5 MPa) compared to CENP-A (6.2 ± 0.4 MPa) and H3 (9.8 ± 0.7 MPa) and that the dynamics of both canonical and CENP-A nucleosomes are preserved and partitioned across the nucleosome pseudodyad. Furthermore, we investigate the mechanism by which the elasticity of these heterotypic nucleosomes augments cryptic binding surfaces. From these analyses, we predict that the heterotypic nucleosome is permissive to the binding of one copy of the kinetochore protein CENP-C while still retaining a closed DNA end configuration required for linker histone H1 to bind. We discuss that the ectopic deposition of CENP-A in cancer by H3.3 chaperones HIRA and DAXX may fortuitously result in hybrid nucleosome formation. Using these results, we propose biological outcomes that might arise when such heterotypic nucleosomes occupy large regions of the genome.

中文翻译：

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最小圆柱分析揭示致癌核小体的机械特性

组蛋白变体调节复制、转录、DNA 损伤修复和染色体分离。尽管被广泛接受为一种范例，但尚未严格证明组蛋白变体编码独特的机械特性。在这里，我们提出了一种称为最小圆柱分析的新理论方法，该方法使用应变波动从全原子分子动力学模拟中确定核小体的杨氏模量。最近，我们针对组蛋白变异核小体的体外单分子纳米压痕验证了这种计算工具。在本报告中，我们进一步扩展最小圆柱体分析来研究已知存在于人类癌细胞中并含有 H3 组蛋白变体 CENP-A 和 H3.3 的混合核小体的生物物理特性。在这里，我们报告说，与 CENP-A (6.2 ± 0.4 MPa) 和 H3 (9.8 ± 0.7 MPa) 相比，异型核小体具有中等弹性 (8.5 ± 0.5 MPa)，并且规范核小体和 CENP-A 核小体的动力学均为保留并分配在核小体假二体上。此外，我们研究了这些异型核小体的弹性增强神秘结合表面的机制。从这些分析中，我们预测异型核小体允许结合一个动粒蛋白 CENP-C 拷贝，同时仍然保留连接组蛋白 H1 结合所需的闭合 DNA 末端构型。我们讨论了 H3.3 伴侣 HIRA 和 DAXX 在癌症中异位沉积 CENP-A 可能偶然导致混合核小体的形成。利用这些结果，我们提出当这种异型核小体占据基因组的大部分区域时可能出现的生物学结果。