PDF(Pubmed)
Abstract：
In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase to form dynamic loops through a process called active loop extrusion. Chromosome conformation capture and imaging experiments have suggested that chromatin adopts a compact structure with limited interpenetration between chromosomes and between chromosomal sections. We developed a theory demonstrating that active loop extrusion causes the apparent fractal dimension of chromatin to cross-over between two and four at contour lengths on the order of 30 kilo-base pairs. The anomalously high fractal dimension [Formula: see text] is due to the inability of extruded loops to fully relax during active extrusion. Compaction on longer contour length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Extrusion-induced compaction segregates TADs such that overlaps between TADs are reduced to less than 35% and increases the entanglement strand of chromatin by up to a factor of 50 to several Mega-base pairs. Furthermore, active loop extrusion couples cohesin motion to chromatin conformations formed by previously extruding cohesins and causes the mean square displacement of chromatin loci during lag times ([Formula: see text]) longer than tens of minutes to be proportional to [Formula: see text]. We validate our results with hybrid molecular dynamics-Monte Carlo simulations and show that our theory is consistent with experimental data. This work provides a theoretical basis for the compact organization of interphase chromatin, explaining the physical reason for TAD segregation and suppression of chromatin entanglements which contribute to efficient gene regulation.
摘要：
在哺乳动物细胞中,粘附蛋白复合物被认为在间期沿染色质易位，通过称为活性环挤出的过程形成动态环。染色体构象捕获和成像实验表明，染色质采用紧密结构，染色体之间和染色体切片之间的相互渗透有限。我们开发了一种理论，证明主动环挤出会导致染色质的表观分形维数在30千碱基对的轮廓长度上在2到4之间交叉。异常高的分形维数[公式：见正文]是由于挤出环在主动挤出过程中无法完全松弛。较长等高线长度尺度上的压实在拓扑关联域(TAD)内延伸，促进远端元件的基因调控。挤出诱导的压实会隔离TAD，使TAD之间的重叠减少到35％以下，并使染色质的缠结链增加多达50倍至几个兆碱基对。此外，主动环挤压将粘附素运动与先前挤压粘附素形成的染色质构象相耦合，并导致染色质基因座在滞后时间（[公式：见正文]）超过数十分钟的均方位移与[公式：见正文]成正比。我们通过混合分子动力学-蒙特卡罗模拟验证了我们的结果，并表明我们的理论与实验数据一致。这项工作为相间染色质的紧密组织提供了理论依据，解释TAD分离和染色质缠结抑制的物理原因，这有助于有效的基因调控。
