Biomolecular condensates have emerged as a powerful new paradigm in cell biology with broad implications to human health and disease, particularly in the nucleus where phase separation is thought to underly elements of chromatin organization and regulation. Specifically, it has been recently reported that phase separation of heterochromatin protein 1alpha (HP1α) with DNA contributes to the formation of condensed chromatin states. HP1α localization to heterochromatic regions is mediated by its binding to specific repressive marks on the tail of histone H3, such as trimethylated lysine 9 on histone H3 (H3K9me3). However, whether epigenetic marks play an active role in modulating the material properties of HP1α and dictating emergent functions of its condensates remains to be understood. Here, we leverage a reductionist system, composed of modified and unmodified histone H3 peptides, HP1α, and DNA, to examine the contribution of specific epigenetic marks to phase behavior of HP1α. We show that the presence of histone peptides bearing the repressive H3K9me3 is compatible with HP1α condensates, whereas peptides containing unmodified residues or bearing the transcriptional activation mark H3K4me3 are incompatible with HP1α phase separation. Using fluorescence microscopy and rheological approaches, we further demonstrate that H3K9me3 histone peptides modulate the dynamics and viscoelastic network properties of HP1α condensates in a concentration-dependent manner. Additionally, in cells exposed to uniaxial strain, we find there to be a decreased ratio of nuclear H3K9me3 to HP1α. These data suggest that HP1α-DNA condensates are viscoelastic materials, whose properties may provide an explanation for the dynamic behavior of heterochromatin in cells and in response to mechanostimulation.

中文翻译：

---

表观遗传标记独特地调节 HP1α 凝聚物的材料特性


生物分子凝聚体已成为细胞生物学中强大的新范例，对人类健康和疾病具有广泛的影响，特别是在细胞核中，相分离被认为是染色质组织和调节的基础要素。具体来说，最近有报道称，异染色质蛋白 1α (HP1α) 与 DNA 的相分离有助于形成浓缩染色质状态。 HP1α 定位到异染色质区域是通过其与组蛋白 H3 尾部的特定抑制标记（例如组蛋白 H3 上的三甲基化赖氨酸 9 (H3K9me3)）的结合来介导的。然而，表观遗传标记是否在调节 HP1α 的材料特性和决定其凝聚物的新兴功能方面发挥积极作用仍有待了解。在这里，我们利用由修饰和未修饰的组蛋白 H3 肽、HP1α 和 DNA 组成的还原系统来检查特定表观遗传标记对 HP1α 相行为的贡献。我们表明，带有抑制性 H3K9me3 的组蛋白肽的存在与 HP1α 缩合物相容，而含有未修饰残基或带有转录激活标记 H3K4me3 的肽与 HP1α 相分离不相容。使用荧光显微镜和流变学方法，我们进一步证明 H3K9me3 组蛋白肽以浓度依赖性方式调节 HP1α 缩合物的动力学和粘弹性网络特性。此外，在暴露于单轴应变的细胞中，我们发现核 H3K9me3 与 HP1α 的比率降低。 这些数据表明 HP1α-DNA 凝聚物是粘弹性材料，其特性可以解释细胞中异染色质的动态行为以及对机械刺激的反应。