Department of Physics, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
Gladstone Institutes of Data Science and Biotechnology, San Francisco, CA 94158.
Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6697-E6706. doi: 10.1073/pnas.1717730115. Epub 2018 Jul 2.
Mammalian chromatin is spatially organized at many scales showing two prominent features in interphase: () alternating regions (1-10 Mb) of active and inactive chromatin that spatially segregate into different compartments, and () domains (<1 Mb), that is, regions that preferentially interact internally [topologically associating domains (TADs)] and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartmentalization is established according to local chromatin states. Here, we use polymer simulations to examine how loop extrusion and compartmental segregation work collectively and potentially interfere in shaping global chromosome organization. A model with differential attraction between euchromatin and heterochromatin leads to phase separation and reproduces compartmentalization as observed in Hi-C. Loop extrusion, essential for TAD formation, in turn, interferes with compartmentalization. Our integrated model faithfully reproduces Hi-C data from puzzling experimental observations where altering loop extrusion also led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed finer compartments, while increased processivity of cohesin strengthened large TADs and reduced compartmentalization; and depletion of the TAD boundary protein CTCF weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. Our results suggest that chromatin organization on the megabase scale emerges from competition of nonequilibrium active loop extrusion and epigenetically defined compartment structure.
哺乳动物染色质在多个尺度上呈现出空间组织，在间期有两个突出的特征：（）活跃和不活跃染色质的交替区域（1-10Mb），这些区域在空间上分离成不同的隔室，以及（）域（<1Mb），即优先在内部相互作用的区域[拓扑关联域（TADs）]，是基因调控的核心。越来越多的证据表明，TADs 是由黏合蛋白主动挤压染色质环形成的，而隔室化则是根据局部染色质状态建立的。在这里，我们使用聚合物模拟来研究环挤出和隔室分离如何共同作用，并可能干扰全局染色体组织的形成。一个在常染色质和异染色质之间具有不同吸引力的模型导致相分离，并再现了 Hi-C 中观察到的隔室化。环挤出对于 TAD 的形成是必不可少的，反过来又会干扰隔室化。我们的综合模型忠实地再现了来自令人费解的实验观察的 Hi-C 数据，在这些观察中，改变环挤出也会导致隔室化的变化。具体来说，染色质相关黏合蛋白的耗竭减少了 TAD 并揭示了更精细的隔室，而黏合蛋白的进程增加增强了大 TAD 并减少了隔室化；TAD 边界蛋白 CTCF 的耗竭削弱了 TAD，而隔室不受影响。我们揭示了这些实验扰动是由环挤出引起的主动混合的一般聚合物现象的特殊情况。我们的结果表明，兆碱基尺度上的染色质组织是由非平衡活性环挤出和表观定义的隔室结构之间的竞争产生的。
