Nonequilibrium models of optimal enhancer function.
Nonequilibrium models of optimal enhancer function.
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DOI：
10.1073/pnas.2006731117
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发表时间：
2020-12-15
影响因子：
11.1
通讯作者：
Tkačik G
中科院分区：
文献类型：
--
作者：
Grah R;Zoller B;Tkačik G
简单的生物物理模型通过预测结合特定调控蛋白的DNA序列的基因表达，成功地描述了细菌的调控密码。类似的简单模型在多细胞生物体中失败了，在多细胞生物体中，调节蛋白非常短暂地结合DNA，但仍然对基因表达进行精确控制。到目前为止，更普遍的“非平衡”模型已经被证明很难分析和连接到数据。在这里，我们通过构建简单的非平衡模型，在已知的实验约束下执行最佳的基因调控，从理论上降低了这种复杂性。在原核生物中，基因调控的热力学模型提供了从启动子序列到基因表达水平的高度定量的映射，这与体内和体外的生物物理测量相一致。在真核生物中，增强子功能的模型还没有达到这样的一致性。在平衡模型中，很难将已报道的短转录因子(TF)在DNA上的停留时间与高度特异性的调控相协调。在非平衡模型中，由于参数数量的爆炸性增长，进展是困难的。在这里，我们通过寻找产生所需调控表型的最小非平衡增强子模型来克服这种复杂性：低Tf停留时间、高特异性和可调的协同性。我们发现，一个额外的参数，可解释为“连接率”，通过它结合的TF与介体成分相互作用，使我们的模型能够逃离均衡界限，并获得最优的调节表型，同时保持与报告的现象学一致，并足够简单，可以从即将到来的实验推断。我们进一步发现，非平衡模型中的高度特异性是与基因表达噪声的权衡，预测突发性动力学--一个实验观察到的真核转录的标志。通过将非平衡增强子模型的庞大参数空间大幅缩小到以最佳方式实现生物功能的更小的子空间，我们提供了一类丰富的模型，这些模型可以在不久的将来从数据中轻松推断出来。
Simple biophysical models successfully describe bacterial regulatory code, by predicting gene expression from DNA sequences that bind specialized regulatory proteins. Analogous simple models fail in multicellular organisms, where regulatory proteins bind DNA very transiently, yet, nevertheless, effect precise control over gene expression. To date, the more general, “nonequilibrium” models have proven difficult to analyze and connect to data. Here, we reduce this complexity theoretically, by constructing simple nonequilibrium models which perform optimal gene regulation within known experimental constraints. In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene-expression levels that is compatible with in vivo and in vitro biophysical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity, and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate,” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics—an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future.
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影响因子：
30.8
作者：
Hammar P;Walldén M;Fange D;Persson F;Baltekin O;Ullman G;Leroy P;Elf J
通讯作者：
Elf J
影响因子：
64.8
作者：
Gertz, Jason;Siggia, Eric D.;Cohen, Barak A.
通讯作者：
Cohen, Barak A.
影响因子：
7.7
作者：
Forcier, Talitha L.;Ayaz, Andalus;Kinney, Justin B.
通讯作者：
Kinney, Justin B.
影响因子：
64.5
作者：
Estrada J;Wong F;DePace A;Gunawardena J
通讯作者：
Gunawardena J
影响因子：
5.6
作者：
BERG, OG;VONHIPPEL, PH
通讯作者：
VONHIPPEL, PH