Cambridge Systems Biology Centre, University of Cambridge Cambridge, UK ; Department of Genetics, University of Cambridge Cambridge, UK.
Front Genet. 2013 Oct 7;4:197. doi: 10.3389/fgene.2013.00197. eCollection 2013.
Transcription factor (TF) molecules translocate by facilitated diffusion (a combination of 3D diffusion around and 1D random walk on the DNA). Despite the attention this mechanism received in the last 40 years, only a few studies investigated the influence of the cellular environment on the facilitated diffusion mechanism and, in particular, the influence of "other" DNA binding proteins competing with the TF molecules for DNA space. Molecular crowding on the DNA is likely to influence the association rate of TFs to their target site and the steady state occupancy of those sites, but it is still not clear how it influences the search in a genome-wide context, when the model includes biologically relevant parameters (such as: TF abundance, TF affinity for DNA and TF dynamics on the DNA). We performed stochastic simulations of TFs performing the facilitated diffusion mechanism, and considered various abundances of cognate and non-cognate TFs. We show that, for both obstacles that move on the DNA and obstacles that are fixed on the DNA, changes in search time are not statistically significant in case of biologically relevant crowding levels on the DNA. In the case of non-cognate proteins that slide on the DNA, molecular crowding on the DNA always leads to statistically significant lower levels of occupancy, which may confer a general mechanism to control gene activity levels globally. When the "other" molecules are immobile on the DNA, we found a completely different behavior, namely: the occupancy of the target site is always increased by higher molecular crowding on the DNA. Finally, we show that crowding on the DNA may increase transcriptional noise through increased variability of the occupancy time of the target sites.
转录因子 (TF) 分子通过易化扩散（三维扩散和 DNA 上的一维随机漫步的组合）进行转运。尽管这种机制在过去的 40 年中受到了关注，但只有少数研究调查了细胞环境对易化扩散机制的影响，特别是“其他”与 TF 分子竞争 DNA 空间的 DNA 结合蛋白的影响。DNA 上的分子拥挤可能会影响 TF 与靶位点的结合速率和这些位点的稳态占据率，但它如何在包含生物学相关参数（如 TF 丰度、TF 与 DNA 的亲和力和 TF 在 DNA 上的动力学）的全基因组范围内的搜索中产生影响仍不清楚。我们对执行易化扩散机制的 TF 进行了随机模拟，并考虑了各种同源和非同源 TF 的丰度。我们表明，对于在 DNA 上移动的障碍物和固定在 DNA 上的障碍物，在 DNA 上具有生物学相关拥挤程度的情况下，搜索时间的变化在统计学上并不显著。对于在 DNA 上滑动的非同源蛋白，DNA 上的分子拥挤总是导致统计学上显著降低的占据水平，这可能为全局控制基因活性水平提供一种普遍机制。当“其他”分子固定在 DNA 上时，我们发现了一种完全不同的行为，即靶位点的占据率总是通过 DNA 上更高的分子拥挤而增加。最后，我们表明 DNA 上的拥挤可能通过增加靶位点占据时间的可变性来增加转录噪声。
