Department of Computational Mathematics, Science and Engineering, Michigan State University, 428 S. Shaw Ln., East Lansing, MI 48824, USA.
Nucleic Acids Res. 2021 Oct 11;49(18):10347-10368. doi: 10.1093/nar/gkab841.
Long-range regulation by distal enhancers plays critical roles in cell-type specific transcriptional programs. Computational predictions of genome-wide enhancer-promoter interactions are still challenging due to limited accuracy and the lack of knowledge on the molecular mechanisms. Based on recent biological investigations, the protein-protein interactions (PPIs) between transcription factors (TFs) have been found to participate in the regulation of chromatin loops. Therefore, we developed a novel predictive model for cell-type specific enhancer-promoter interactions by leveraging the information of TF PPI signatures. Evaluated by a series of rigorous performance comparisons, the new model achieves superior performance over other methods. The model also identifies specific TF PPIs that may mediate long-range regulatory interactions, revealing new mechanistic understandings of enhancer regulation. The prioritized TF PPIs are associated with genes in distinct biological pathways, and the predicted enhancer-promoter interactions are strongly enriched with cis-eQTLs. Most interestingly, the model discovers enhancer-mediated trans-regulatory links between TFs and genes, which are significantly enriched with trans-eQTLs. The new predictive model, along with the genome-wide analyses, provides a platform to systematically delineate the complex interplay among TFs, enhancers and genes in long-range regulation. The novel predictions also lead to mechanistic interpretations of eQTLs to decode the genetic associations with gene expression.
远端增强子的长程调控在细胞类型特异性转录程序中起着关键作用。由于准确性有限以及对分子机制缺乏了解，全基因组增强子-启动子相互作用的计算预测仍然具有挑战性。基于最近的生物学研究，发现转录因子（TFs）之间的蛋白质-蛋白质相互作用（PPIs）参与了染色质环的调控。因此，我们通过利用 TF PPI 特征的信息，开发了一种用于细胞类型特异性增强子-启动子相互作用的新型预测模型。通过一系列严格的性能比较评估，该新模型的性能优于其他方法。该模型还确定了可能介导长程调控相互作用的特定 TF PPI，揭示了增强子调控的新机制理解。优先 TF PPI 与不同生物学途径中的基因相关，预测的增强子-启动子相互作用强烈富集 cis-eQTLs。最有趣的是，该模型发现了 TF 和基因之间的增强子介导的跨调控联系，这些联系与 trans-eQTLs 显著富集。新的预测模型以及全基因组分析为系统描绘长程调控中 TF、增强子和基因之间的复杂相互作用提供了一个平台。新的预测还导致了对 eQTL 的机制解释，以解码与基因表达相关的遗传关联。
