School of Physics and Astronomy, University of Edinburgh, Peter Guthrie Tait Road, Edinburgh EH9 3FD, UK.
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
Nucleic Acids Res. 2024 Aug 12;52(14):8184-8192. doi: 10.1093/nar/gkae484.
The insertion of DNA elements within genomes underpins both genetic diversity and disease when unregulated. Most of DNA insertions are not random and the physical mechanisms underlying the integration site selection are poorly understood. Here, we perform Molecular Dynamics simulations to study the insertion of DNA elements, such as viral DNA or transposons, into naked DNA or chromatin substrates. More specifically, we explore the role of loops within the polymeric substrate and discover that they act as 'geometric catalysts' for DNA integration by reducing the energy barrier for substrate deformation. Additionally, we discover that the 1D pattern and 3D conformation of loops have a marked effect on the distribution of integration sites. Finally, we show that loops may compete with nucleosomes to attract DNA integrations. These results may be tested in vitro and they may help to understand patterns of DNA insertions with implications in genome evolution and engineering.
DNA 元件在基因组内的插入是遗传多样性和疾病发生的基础，尤其是在不受调控的情况下。大多数 DNA 插入并非随机发生，整合位点选择的物理机制尚不清楚。在这里，我们通过分子动力学模拟来研究 DNA 元件（如病毒 DNA 或转座子）插入裸露 DNA 或染色质底物的过程。更具体地说，我们探索了聚合底物内环的作用，并发现它们通过降低底物变形的能垒，充当 DNA 整合的“几何催化剂”。此外，我们发现环的 1D 模式和 3D 构象对整合位点的分布有显著影响。最后，我们表明环可能与核小体竞争以吸引 DNA 整合。这些结果可以在体外进行测试，它们可能有助于理解与基因组进化和工程相关的 DNA 插入模式。
