Single-cell chromatin studies provide insights into how chromatin structure relates to functions of individual cells. However, balancing high-resolution and genome-wide coverage remains challenging. We describe a computational method for the reconstruction of large 3D-ensembles of single-cell (sc) chromatin conformations from population Hi-C that we apply to study embryogenesis in Drosophila. With minimal assumptions of physical properties and without adjustable parameters, our method generates large ensembles of chromatin conformations via deep-sampling. Our method identifies specific interactions, which constitute 5-6% of Hi-C frequencies, but surprisingly are sufficient to drive chromatin folding, giving rise to the observed Hi-C patterns. Modeled sc-chromatins quantify chromatin heterogeneity, revealing significant changes during embryogenesis. Furthermore, >50% of modeled sc-chromatin maintain topologically associating domains (TADs) in early embryos, when no population TADs are perceptible. Domain boundaries become fixated during development, with strong preference at binding-sites of insulator-complexes upon the midblastula transition. Overall, high-resolution 3D-ensembles of sc-chromatin conformations enable further in-depth interpretation of population Hi-C, improving understanding of the structure-function relationship of genome organization.

中文翻译：

---

果蝇胚胎发生过程中染色质集合的高分辨率单细胞3D模型。

单细胞染色质研究提供了关于染色质结构如何与单个细胞功能相关的见解。然而，在高分辨率和全基因组覆盖之间取得平衡仍然是挑战。我们描述了一种用于从人口Hi-C重建单细胞（sc）染色质构象的大型3D集成体的计算方法，该方法可用于研究果蝇的胚胎发生。在最小限度的物理特性假设和无可​​调整参数的情况下，我们的方法通过深度采样生成了大量染色质构象。我们的方法确定了特定的相互作用，这些相互作用构成Hi-C频率的5-6％，但令人惊讶地足以驱动染色质折叠，从而产生了观察到的Hi-C模式。建模的sc染色质可量化染色质异质性，揭示胚胎发生过程中的显着变化。此外，当没有群体TAD可以感知时，> 50％的建模sc-染色质在早期胚胎中保持拓扑关联域（TAD）。区域边界在发育过程中被固定，在中胚层过渡时强烈偏好绝缘子复合体的结合位点。总体而言，sc-染色质构象的高分辨率3D集成可进一步深入解释Hi-C种群，从而增进了对基因组组织的结构-功能关系的了解。