Transcription factor interactions explain the context-dependent activity of CRX binding sites.
Transcription factor interactions explain the context-dependent activity of CRX binding sites.
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DOI：
10.1371/journal.pcbi.1011802
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发表时间：
2024-01
影响因子：
4.3
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文献类型：
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转录因子结合位点（TFBS）对顺式调控元件（CRE）活性的影响取决于局部序列背景。在视杆光感受器中，转录因子（TF）锥-杆同源框（CRX）的结合位点出现在增强子和沉默子中，但是决定CRX结合位点是否有助于转录的激活或抑制的序列背景尚不清楚。为了研究CRX位点的上下文依赖性活性，我们将基于神经网络的模型拟合到由光感受器TFBS组成的合成克雷斯的活性。该模型显示，CRX结合位点始终作出积极的，独立的贡献，CRE活性，而网站之间的负同型相互作用导致克雷斯组成的多个CRX网站作为沉默剂。负同型相互作用的影响可以通过存在其他TFBS来克服，这些TFBS要么与CRX位点协同相互作用，要么对活性做出独立的正贡献。因此，CRX位点的上下文依赖性活性由正异型相互作用、TFBS的独立贡献和负同型相互作用之间的平衡决定。我们的研究结果解释了基因组CRX结合增强子和沉默子之间观察到的活性模式，并表明增强子可能需要不同的TFBS来克服TFBS之间的负同型相互作用。转录因子通过与调节DNA中的位点结合来控制不同细胞类型中的基因表达。相同的转录因子在不同的DNA位点结合时会对基因表达产生不同的影响，但单个因子如何产生不同的影响尚不清楚。光感受器转录因子CRX激活从含有CRX结合位点的几个拷贝的调节DNA的表达，而当存在许多结合位点拷贝时，它抑制表达。我们模拟了CRX和其他因素的结合位点的数量和排列如何影响基因表达，使用合成调控DNA元件库的数据。该模型表明，单个转录因子结合位点本身增加表达，但同一位点的多个拷贝之间的相互作用降低表达。我们的研究结果概括了转录因子和组织，表明这是一个普遍的原则，可能有助于解释不同组织的表达模式。该模型解释了结合位点之间的相互作用如何允许单个转录因子对相同细胞类型中的基因表达产生对比效应。
The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs. Transcription factors control gene expression in different cell types by binding to sites in regulatory DNA. The same transcription factor when bound at different DNA sites will have different effects on gene expression, but how a single factor can produce divergent effects is unclear. The photoreceptor transcription factor CRX activates expression from regulatory DNA that harbors few copies of a CRX binding site, while it represses expression when many binding site copies are present. We modeled how the number and arrangement of binding sites for CRX and other factors affect gene expression, using data from libraries of synthetic regulatory DNA elements. The model shows that individual transcription factor binding sites increase expression on their own, but interactions between multiple copies of the same site decrease expression. Our results generalize across transcription factors and tissues, suggesting that this is a general principle that might help explain differing patterns of expression across tissues. The model explains how interactions between binding sites allow a single transcription factor to have contrasting effects on gene expression in the same cell type.
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