Cohesin-dependent chromosome loop extrusion is limited by transcription and stalled replication forks [RNA-seq]

Genome function depends on regulated chromosome folding, and loop extrusion by the protein complex cohesin is essential for this multilayered organization. The chromosomal positioning of cohesin is controlled by transcription, and the complex also localizes to stalled replication forks. However, the role of transcription and replication in chromosome looping remains unclear. Here, we show that reduction of chromosome-bound RNA polymerase weakens normal cohesin loop extrusion boundaries, allowing cohesin to form new long-range chromosome cis interactions. Stress response genes activated by transcription inhibition are also shown to act as new loop extrusion boundaries. Furthermore, cohesin loop extrusion during early S-phase is jointly controlled by transcription and replication units. Together, the results reveal that replication and transcription machineries are chromosome folding regulators that block the progression of loop-extruding cohesin, opening for new perspectives on cohesin’s roles in genome function and stability.基因组功能依赖于受调控的染色体折叠，而蛋白质复合物黏连蛋白（cohesin）介导的环挤出（loop extrusion）对于这种多层级的染色体组织形式至关重要。黏连蛋白的染色体定位受转录过程调控，同时该复合物也会定位于停滞的复制叉。然而，转录与复制在染色体环形成过程中所发挥的作用仍未明确。本研究发现，染色体结合型RNA聚合酶（RNA polymerase）的水平降低会削弱正常黏连蛋白环挤出的边界，使得黏连蛋白能够形成新的长距离染色体顺式相互作用（cis interactions）。经转录抑制激活的应激反应基因，同样可作为新的环挤出边界。此外，S早期的黏连蛋白环挤出过程同时受转录单元与复制单元的共同调控。综上，本研究结果揭示，复制与转录装置是一类可阻断环挤出型黏连蛋白行进的染色体折叠调控因子，为理解黏连蛋白在基因组功能与基因组稳定性中的作用提供了全新视角。