Shadow enhancers mediate trade-offs between transcriptional noise and fidelity.
Shadow enhancers mediate trade-offs between transcriptional noise and fidelity.
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DOI：
10.1371/journal.pcbi.1011071
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发表时间：
2023-05
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
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增强子是结合转录因子（TFs）并调节靶基因表达的调控DNA片段。阴影增强子是在空间和时间上调控同一靶基因的两个或多个增强子，与大多数动物发育基因有关。这些多增强子系统可以比单增强子系统驱动更一致的转录。然而，为什么阴影增强子TF结合位点分布在多个增强子而不是单个大增强子中，目前尚不清楚。在这里，我们使用计算方法来研究具有不同数量的TF结合位点和增强子的系统。我们采用随机动力学的化学反应网络来确定转录噪声和保真度的趋势，这是增强剂的两个关键性能目标。这表明，虽然加性阴影增强剂在噪声和保真度方面与单增强剂没有区别，但子和超加性阴影增强剂具有单增强剂所不具备的噪声和保真度权衡。我们还使用我们的计算方法来比较单个增强子的复制和分裂作为产生阴影增强子的机制，并发现增强子的复制可以降低噪声并提高保真度，尽管以增加RNA产生的代谢成本为代价。增强子相互作用的饱和机制类似地改善了这两个指标。综上所述，这项工作强调了影子增强子系统的存在可能有几个原因：遗传漂变或增强子关键功能的调整，包括转录保真度、噪声和输出。在发育过程中，细胞根据不同的信号承担不同的命运，包括结合DNA增强子区域的转录因子蛋白质。增强子可以与启动子相互作用以控制靶基因的转录。许多发育基因有多个看似冗余的增强子，称为影子增强子。当每个单独的增强子与不同的转录因子结合时，影子增强子可以比单个增强子驱动更少的噪声基因表达。这允许在转录因子输入的扰动的缓冲。然而，在这个前提下，由不同转录因子结合的单个大增强子也应该能够缓冲扰动。那么为什么暗影增强术如此盛行呢？Fletcher等人开发了增强子介导转录的计算模型，该模型在增强子和转录因子结合位点的数量上有所不同。他们分析了有和没有阴影增强剂的系统的转录特性。模型显示，阴影增强剂可以提供更广泛的可能的转录特性。这种计算方法使阴影增强特性的探索比实验可行的更广泛，并可能指导未来的实验。鉴于它们在发育基因调控中的普遍存在，对阴影增强子的研究可能有助于更好地理解发育增强子中某些突变的致病性。
Enhancers are stretches of regulatory DNA that bind transcription factors (TFs) and regulate the expression of a target gene. Shadow enhancers are two or more enhancers that regulate the same target gene in space and time and are associated with most animal developmental genes. These multi-enhancer systems can drive more consistent transcription than single enhancer systems. Nevertheless, it remains unclear why shadow enhancer TF binding sites are distributed across multiple enhancers rather than within a single large enhancer. Here, we use a computational approach to study systems with varying numbers of TF binding sites and enhancers. We employ chemical reaction networks with stochastic dynamics to determine the trends in transcriptional noise and fidelity, two key performance objectives of enhancers. This reveals that while additive shadow enhancers do not differ in noise and fidelity from their single enhancer counterparts, sub- and superadditive shadow enhancers have noise and fidelity trade-offs not available to single enhancers. We also use our computational approach to compare the duplication and splitting of a single enhancer as mechanisms for the generation of shadow enhancers and find that the duplication of enhancers can decrease noise and increase fidelity, although at the metabolic cost of increased RNA production. A saturation mechanism for enhancer interactions similarly improves on both of these metrics. Taken together, this work highlights that shadow enhancer systems may exist for several reasons: genetic drift or the tuning of key functions of enhancers, including transcription fidelity, noise and output. During development, cells assume different fates based upon signals, including transcription factor proteins that bind to regions of the DNA called enhancers. Enhancers can interact with promoters to control the transcription of a target gene. Many developmental genes have multiple, seemingly redundant enhancers called shadow enhancers. When each separate enhancer is bound by distinct transcription factors, shadow enhancers can drive less noisy gene expression than single enhancers. This allows for the buffering of perturbations in the transcription factor inputs. However, under this premise, a single large enhancer bound by distinct transcription factors should also be capable of buffering perturbations. Why then are shadow enhancers so prevalent? Fletcher et al. developed computational models of enhancer-mediated transcription that vary in the numbers of enhancers and transcription factor binding sites. They analyzed transcriptional properties in systems with and without shadow enhancers. The models revealed that shadow enhancers can provide a wider landscape of possible transcriptional properties. This computational approach enabled a broader exploration of shadow enhancer properties than is feasible experimentally and may guide future experimentation. Given their prevalence in developmental gene regulation, investigation of shadow enhancers may lead to a better understanding on the pathogenicity of certain mutations found in developmental enhancers.
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影响因子：
2.7
作者：
Degenhardt KR;Milewski RC;Padmanabhan A;Miller M;Singh MK;Lang D;Engleka KA;Wu M;Li J;Zhou D;Antonucci N;Li L;Epstein JA
通讯作者：
Epstein JA
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.2006731117
发表时间：
2020-12-15
影响因子：
11.1
作者：
Grah R;Zoller B;Tkačik G
通讯作者：
Tkačik G
影响因子：
16.6
作者：
Cao Z;Grima R
通讯作者：
Grima R
影响因子：
4.6
作者：
Jeong, YS;El-Jaick, K;Epstein, DJ
通讯作者：
Epstein, DJ