Department of Computer Science, Virginia Tech, Blacksburg, VA, 24061, USA.
Department of Entomology, Virginia Tech, Blacksburg, VA, 24061, USA.
Epigenetics Chromatin. 2023 May 30;16(1):21. doi: 10.1186/s13072-023-00492-9.
Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of three-dimensional (3D) chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.
We have developed a coarse-grained dynamical model of D. melanogaster nuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD-NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. The simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development. Predicted positioning of all LADs at the NE is highly dynamic-the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome, which also has the same strong effect on the predicted positioning of individual TADs -- higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD-TAD interactions compared to the lamin depleted nuclei, where a small (0.5 kT) increase of cross-type TAD-TAD interactions doubles the chromatin density in the central nucleus region.
A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD-NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD-TAD interactions.
拓扑关联域（TAD）之间以及核膜（NE）与染色质相关域（LAD）之间的相互作用预计将影响三维（3D）染色质结构和动力学的各个方面；然而，相关的全基因组实验仍然难以提供具有统计学意义的结论。
我们开发了一种粗粒度的果蝇核 TAD 分辨率动力模型，该模型明确考虑了四个不同的 TAD 和 LAD-NE 相互作用的表观遗传类。该模型通过参数化来再现野生型（WT）核的实验 Hi-C 图谱；它描述了间期 G1 期染色质的时间演化。模拟包括一组对应于实验观察到的染色体臂多种可能相互排列的核。该模型经过多个不同实验的多个结构特征进行了验证，这些实验没有用于模型开发。所有 LAD 在 NE 上的预测定位高度动态——同一个 LAD 在间期可以多次附着、脱离并远离 NE。尽管在模型中所有 LAD 与 NE 的亲和力相同，但 LAD 与 NE 接触的概率相差一个数量级。这些概率主要由 LAD 沿基因组的高度可变局部线性密度决定，这对单个 TAD 的预测定位也有同样的强烈影响——TAD 靠近 NE 的概率更高在很大程度上取决于围绕此 TAD 的 LAD 线性密度更高。LAD 沿染色体链的分布在维持染色质的非随机平均整体结构方面起着显著作用。与 lamin 耗尽核相比，WT 核中 LAD 与 NE 的相对高亲和力大大降低了全局径向染色质分布对 TAD-TAD 相互作用强度变化的敏感性，在 lamin 耗尽核中，交叉型 TAD-TAD 相互作用的微小（0.5 kT）增加将使核中心区域的染色质密度增加一倍。
整个果蝇基因组的动力模型对多个具有生物学意义的全基因组进行了预测。LAD 沿染色质链的分布影响其与 NE 接触的概率和高度移动 TAD 的径向定位，在创建染色质的非随机平均整体结构方面起着显著作用。我们推测，LAD-NE 相互作用的一个重要作用是稳定全局染色质结构，以抵御 TAD-TAD 相互作用在细胞间不可避免的变化。
