Using molecular dynamics simulations, we show here that growing plectonemes resulting from transcription-induced supercoiling have the ability to actively push cohesin rings along chromatin fibres. The pushing direction is such that within each topologically associating domain (TAD) cohesin rings forming handcuffs move from the source of supercoiling, constituted by RNA polymerase with associated DNA topoisomerase TOP1, towards borders of TADs, where supercoiling is released by topoisomerase TOPIIB. Cohesin handcuffs are pushed by continuous flux of supercoiling that is generated by transcription and is then progressively released by action of TOPIIB located at TADs borders. Our model explains what can be the driving force of chromatin loop extrusion and how it can be ensured that loops grow quickly and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites. We discuss the role of supercoiling in stimulating enhancer promoter contacts and propose that transcription of eRNA sends the first wave of supercoiling that can activate mRNA transcription in a given TAD.

中文翻译：

---

转录诱导的超螺旋是间期染色体 TAD 形成过程中染色质环挤出的驱动力


使用分子动力学模拟，我们在这里表明，由转录诱导的超螺旋产生的不断生长的皮线体具有沿着染色质纤维主动推动粘连蛋白环的能力。推动方向是这样的，即在每个拓扑关联结构域 (TAD) 内，形成手铐的粘连环从超螺旋源（由 RNA 聚合酶和相关 DNA 拓扑异构酶 TOP1 构成）移动到 TAD 的边界，其中超螺旋由拓扑异构酶 TOPIIB 释放。粘连蛋白手铐由转录产生的连续超螺旋通量推动，然后通过位于 TAD 边界的 TOPIIB 的作用逐渐释放。我们的模型解释了染色质环挤出的驱动力以及如何确保环快速且朝着良好的方向生长。此外，超螺旋驱动的环挤出机制与早期的解释一致，早期的解释提出了为什么侧翼有会聚 CTCF 结合位点的 TAD 比侧翼有不同 CTCF 结合位点的 TAD 形成更稳定的染色质环。我们讨论了超螺旋在刺激增强子启动子接触中的作用，并提出 eRNA 的转录发出第一波超螺旋，可以激活给定 TAD 中的 mRNA 转录。