Jeppsson Kristian, Sakata Toyonori, Nakato Ryuichiro, Milanova Stefina, Shirahige Katsuhiko, Björkegren Camilla
Karolinska Institutet, Department of Biosciences and Nutrition, Neo, Hälsovägen 7c, 141 83 Huddinge, Sweden.
Karolinska Institutet, Department of Cell and Molecular Biology, Biomedicum, Tomtebodavägen 16, 171 77 Stockholm, Sweden.
Sci Adv. 2022 Jun 10;8(23):eabn7063. doi: 10.1126/sciadv.abn7063.
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 induced 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介导的环挤压对于这种多层组织至关重要。黏连蛋白的染色体定位由转录控制，并且该复合物也定位于停滞的复制叉处。然而，转录和复制在染色体环化中的作用仍不清楚。在这里，我们表明，与染色体结合的RNA聚合酶减少会削弱正常的黏连蛋白环挤压边界，使黏连蛋白能够形成新的长距离染色体顺式相互作用。转录抑制诱导的应激反应基因也被证明可作为新的环挤压边界。此外，在S期早期，黏连蛋白环挤压由转录和复制单元共同控制。这些结果共同揭示，复制和转录机制是染色体折叠调节剂，它们会阻止环挤压黏连蛋白的推进，为深入了解黏连蛋白在基因组功能和稳定性中的作用开辟了新视角。
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