Genomics Bioinformatics and Computational Biology, Virginia Tech, Blacksburg, VA, 24061, USA.
Department of Entomology, Virginia Tech, Blacksburg, VA, 24061, USA.
Epigenetics Chromatin. 2018 Jan 22;11(1):3. doi: 10.1186/s13072-018-0173-5.
It is well recognized that the interphase chromatin of higher eukaryotes folds into non-random configurations forming territories within the nucleus. Chromosome territories have biologically significant properties, and understanding how these properties change with time during lifetime of the cell is important. Chromosome-nuclear envelope (Chr-NE) interactions play a role in epigenetic regulation of DNA replication, repair, and transcription. However, their role in maintaining chromosome territories remains unclear.
We use coarse-grained molecular dynamics simulations to study the effects of Chr-NE interactions on the dynamics of chromosomes within a model of the Drosophila melanogaster regular (non-polytene) interphase nucleus, on timescales comparable to the duration of interphase. The model simulates the dynamics of chromosomes bounded by the NE. Initially, the chromosomes in the model are prearranged in fractal-like configurations with physical parameters such as nucleus size and chromosome persistence length taken directly from experiment. Time evolution of several key observables that characterize the chromosomes is quantified during each simulation: chromosome territories, chromosome entanglement, compactness, and presence of the Rabl (polarized) chromosome arrangement. We find that Chr-NE interactions help maintain chromosome territories by slowing down and limiting, but not eliminating, chromosome entanglement on biologically relevant timescales. At the same time, Chr-NE interactions have little effect on the Rabl chromosome arrangement as well as on how chromosome compactness changes with time. These results are rationalized by simple dimensionality arguments, robust to model details. All results are robust to the simulated activity of topoisomerase, which may be present in the interphase cell nucleus.
Our study demonstrates that Chr-NE attachments may help maintain chromosome territories, while slowing down and limiting chromosome entanglement on biologically relevant timescales. However, Chr-NE attachments have little effect on chromosome compactness or the Rabl chromosome arrangement.
众所周知，高等真核生物的间期染色质折叠成非随机构象，在核内形成域。染色体域具有重要的生物学特性，了解这些特性在细胞寿命期间如何随时间变化是很重要的。染色体-核膜（Chr-NE）相互作用在 DNA 复制、修复和转录的表观遗传调控中发挥作用。然而，它们在维持染色体域方面的作用尚不清楚。
我们使用粗粒分子动力学模拟来研究 Chr-NE 相互作用对果蝇正常（非多线体）间期核模型中染色体动力学的影响，模拟时间尺度与间期持续时间相当。该模型模拟了由 NE 限制的染色体的动力学。最初，模型中的染色体以类分形的构象预先排列，物理参数如核大小和染色体持续长度直接来自实验。在每次模拟中，量化了几个特征染色体的关键观测值的时间演化：染色体域、染色体缠结、紧凑性和 Rabl（极化）染色体排列的存在。我们发现 Chr-NE 相互作用通过减缓和限制，但不能消除，在生物相关的时间尺度上限制染色体缠结，有助于维持染色体域。与此同时，Chr-NE 相互作用对 Rabl 染色体排列以及染色体紧凑性随时间的变化几乎没有影响。这些结果通过简单的维度论证得到了合理化，对模型细节具有鲁棒性。所有结果对间期细胞核中可能存在的拓扑异构酶的模拟活性都是稳健的。
我们的研究表明，Chr-NE 附着可能有助于维持染色体域，同时在生物相关的时间尺度上减缓和限制染色体缠结。然而，Chr-NE 附着对染色体紧凑性或 Rabl 染色体排列几乎没有影响。
