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arXiv 1506.06925q-bio.MNphysics.bio-ph
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全局串扰对基因调控的内在限制

Intrinsic limits to gene regulation by global crosstalk

Tamar Friedlander, Roshan Prizak, Călin C. Guet, Nicholas H. Barton, Gašper Tkačik

摘要:

基因调控依赖于转录因子(TF)- DNA相互作用的特异性。在平衡状态下,有限的特异性可能导致串扰:一种调节状态,其中基因由于非同源TF-DNA相互作用而被错误激活或保持错误的失活状态。我们提出了一个易于处理的生物物理模型的全球串扰,许多基因同时受到许多TF。我们表明,在最简单的监管情况下,串扰的严重程度的下限可以分析来自单独的(共)调节基因的数量和一个合适的参数,描述结合位点的相似性。估计表明,串扰可能是一个重大的挑战,生物低特异性TF,如后生动物,除非他们使用适当的监管计划。强协同性大大降低串扰,而联合调节激活剂和抑制剂,令人惊讶的是,没有;此外,某些微观细节启动子架构出现作为全球重要的决定因素的串扰强度。我们的研究结果表明,串扰施加了一种新型的全局约束的功能和进化的调控网络,这是定性不同的已知的约束作用在个人的基因调控元件的水平。

英文摘要:

Gene regulation relies on the specificity of transcription factor (TF) - DNA interactions. In equilibrium, limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF-DNA interactions or remains erroneously inactive. We present a tractable biophysical model of global crosstalk, where many genes are simultaneously regulated by many TFs. We show that in the simplest regulatory scenario, a lower bound on crosstalk severity can be analytically derived solely from the number of (co)regulated genes and a suitable parameter that describes binding site similarity. Estimates show that crosstalk could present a significant challenge for organisms with low-specificity TFs, such as metazoans, unless they use appropriate regulation schemes. Strong cooperativity substantially decreases crosstalk, while joint regulation by activators and repressors, surprisingly, does not; moreover, certain microscopic details about promoter architecture emerge as globally important determinants of crosstalk strength. Our results suggest that crosstalk imposes a new type of global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints acting at the level of individual gene regulatory elements.

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