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arXiv 1909.09478q-bio.SCphysics.bio-ph
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人类染色体蛋白质目标搜索模型

Modelling Protein Target-Search in Human Chromosomes

Markus Nyberg, Tobias Ambjörnsson, Per Stenberg, and Ludvig Lizana

发表信息：
Phys. Rev. Research 3, 013055 (2021)
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摘要：

当关键蛋白质识别并结合短DNA序列时，细胞中的几个过程，如基因调控，就开始了。然而，由于这些序列可能比基因组短数亿倍，因此很难通过简单的扩散找到它们：扩散限制的结合率可能会低估$in~vitro$测量值达几个数量级。此外，如果DNA是卷曲的而不是直的，则速率增加。在这里，我们模拟了$in~vivo$在哺乳动物细胞中的工作原理。我们使用染色质染色质接触数据从国家的最先进的Hi-C实验映射到网络问题的蛋白质目标搜索。节点表示DNA片段，并且链接的权重与测量的接触概率成比例。然后，我们提出了一个主方程的密度搜索蛋白质，使我们能够计算整个基因组的关联率分析。对于比率高的片段，我们发现它们富含活性基因并且具有高RNA表达水平。本文提出，DNA的三维构象是重要的蛋白质搜索时间$in~vivo$，并提供了一种方法来解释蛋白质结合的档案，在真核生物中，不能解释的DNA序列本身。

英文摘要：

Several processes in the cell, such as gene regulation, start when key proteins recognise and bind to short DNA sequences. However, as these sequences can be hundreds of million times shorter than the genome, they are hard to find by simple diffusion: diffusion-limited association rates may underestimate $in~vitro$ measurements up to several orders of magnitude. Moreover, the rates increase if the DNA is coiled rather than straight. Here we model how this works $in~vivo$ in mammalian cells. We use chromatin-chromatin contact data from state-of-the-art Hi-C experiments to map the protein target-search onto a network problem. The nodes represent a DNA segment and the weight of the links is proportional to measured contact probabilities. We then put forward a master equation for the density of searching protein that allows us to calculate the association rates across the genome analytically. For segments where the rates are high, we find that they are enriched with active genes and have high RNA expression levels. This paper suggests that the DNA's 3D conformation is important for protein search times $in~vivo$ and offers a method to interpret protein-binding profiles in eukaryotes that cannot be explained by the DNA sequence itself.

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