Genome Architecture, Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain.
Universidad Pompeu Fabra (UPF), 08003, Barcelona, Spain.
Nat Commun. 2018 Apr 30;9(1):1740. doi: 10.1038/s41467-018-04130-x.
All organisms regulate transcription of their genes. To understand this process, a complete understanding of how transcription factors find their targets in cellular nuclei is essential. The DNA sequence and other variables are known to influence this binding, but the distribution of transcription factor binding patterns remains mostly unexplained in metazoan genomes. Here, we investigate the role of chromosome conformation in the trajectories of transcription factors. Using molecular dynamics simulations, we uncover the principles of their diffusion on chromatin. Chromosome contacts play a conflicting role: at low density they enhance transcription factor traffic, but at high density they lower it by volume exclusion. Consistently, we observe that in human cells, highly occupied targets, where protein binding is promiscuous, are found at sites engaged in chromosome loops within uncompacted chromatin. In summary, we provide a framework for understanding the search trajectories of transcription factors, highlighting the key contribution of genome conformation.
所有生物都调节其基因的转录。为了理解这个过程，全面了解转录因子如何在细胞核中找到其靶标是至关重要的。DNA 序列和其他变量已知会影响这种结合，但真核生物基因组中转录因子结合模式的分布在很大程度上仍未得到解释。在这里，我们研究了染色体构象在转录因子轨迹中的作用。使用分子动力学模拟，我们揭示了它们在染色质上扩散的原理。染色体接触起着相互矛盾的作用：在低密度时，它们会增强转录因子的流量，但在高密度时，它们会通过体积排斥降低流量。一致地，我们观察到在人类细胞中，高度占据的靶标，其中蛋白质结合是混杂的，位于未压缩染色质中参与染色体环的位点处。总之，我们提供了一个理解转录因子搜索轨迹的框架，强调了基因组构象的关键贡献。
