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1. A systematic study of motif pairs that may facilitate enhancer–promoter interactions

   https://doi.org/10.1515/jib-2021-0038  

   Wang, Saidi; Hu, Haiyan; Li, Xiaoman (August 2021, Journal of Integrative Bioinformatics)

   Abstract Pairs of interacting transcription factors (TFs) have previously been shown to bind to enhancers and promoters and contribute to their physical interactions. However, to date, we have limited knowledge about such TF pairs. To fill this void, we systematically studied the co-occurrence of TF-binding motifs in interacting enhancer–promoter (EP) pairs in seven human cell lines. We discovered 423 motif pairs that significantly co-occur in enhancers and promoters of interacting EP pairs. We demonstrated that these motif pairs are biologically meaningful and significantly enriched with motif pairs of known interacting TF pairs. We also showed that the identified motif pairs facilitated the discovery of the interacting EP pairs. The developed pipeline, EPmotifPair, together with the predicted motifs and motif pairs, is available at https://doi.org/10.6084/m9.figshare.14192000 . Our study provides a comprehensive list of motif pairs that may contribute to EP physical interactions, which facilitate generating meaningful hypotheses for experimental validation. 

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2. Long G4-rich enhancers target promoters via a G4 DNA-based mechanism

   https://doi.org/10.1093/nar/gkae1180  

   DeMeis, Jeffrey D; Roberts, Justin T; Delcher, Haley A; Godang, Noel L; Coley, Alexander B; Brown, Cana L; Shaw, Michael H; Naaz, Sayema; Dahal, Ayush; Alqudah, Shahem Y; et al (January 2025, Nucleic Acids Research)

   Abstract Several studies have now described instances where G-rich sequences in promoters and enhancers regulate gene expression through forming G-quadruplex (G4) structures. Relatedly, our group recently identified 301 long genomic stretches significantly enriched for minimal G4 motifs (LG4s) in humans and found the majority of these overlap annotated enhancers, and furthermore, that the promoters regulated by these LG4 enhancers are similarly enriched with G4-capable sequences. While the generally accepted model for enhancer:promoter specificity maintains that interactions are dictated by enhancer- and promoter-bound transcriptional activator proteins, the current study tested an alternative hypothesis: that LG4 enhancers interact with cognate promoters via a direct G4:G4 DNA-based mechanism. This work establishes the nuclear proximity of LG4 enhancer:promoter pairs, biochemically demonstrates the ability of individual LG4 single-stranded DNAs (ssDNAs) to directly interact target promoter ssDNAs, and confirms that these interactions, as well as the ability of LG4 enhancers to activate target promoters in culture, are mediated by G4 DNA. 

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3. Supervised learning of enhancer–promoter specificity based on genome-wide perturbation studies highlights areas for improvement in learning

   https://doi.org/10.1093/bioinformatics/btae367  

   Barth, Dylan; Van, Richard; Cardwell, Jonathan; Han, Mira V (June 2024, Bioinformatics)

   Mathelier, Anthony (Ed.)

   Abstract MotivationUnderstanding the rules that govern enhancer-driven transcription remains a central unsolved problem in genomics. Now with multiple massively parallel enhancer perturbation assays published, there are enough data that we can utilize to learn to predict enhancer–promoter (EP) relationships in a data-driven manner. ResultsWe applied machine learning to one of the largest enhancer perturbation studies integrated with transcription factor (TF) and histone modification ChIP-seq. The results uncovered a discrepancy in the prediction of genome-wide data compared to data from targeted experiments. Relative strength of contact was important for prediction, confirming the basic principle of EP regulation. Novel features such as the density of the enhancers/promoters in the genomic region was found to be important, highlighting our lack of understanding on how other elements in the region contribute to the regulation. Several TF peaks were identified that improved the prediction by identifying the negatives and reducing False Positives. In summary, integrating genomic assays with enhancer perturbation studies increased the accuracy of the model, and provided novel insights into the understanding of enhancer-driven transcription. Availability and implementationThe trained models, data, and the source code are available at http://doi.org/10.5281/zenodo.11290386 and https://github.com/HanLabUNLV/sleps. 

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4. Putative looping factor ZNF143/ZFP143 is an essential transcriptional regulator with no looping function

   https://doi.org/10.1016/j.molcel.2024.11.032  

   Narducci, Domenic N; Hansen, Anders S (January 2025, Molecular Cell)

   Interactions between distal loci, including those involving enhancers and promoters, are a central mechanism of gene regulation in mammals, yet the protein regulators of these interactions remain largely undetermined. The zinc-finger transcription factor (TF) ZNF143/ZFP143 has been strongly implicated as a regulator of chromatin interactions, functioning either with or without CTCF. However, how ZNF143/ZFP143 functions as a looping factor is not well understood. Here, we tagged both CTCF and ZNF143/ZFP143 with dual-purpose degron/imaging tags to combinatorially assess their looping function and effect on each other. We find that ZNF143/ZFP143, contrary to prior reports, possesses no general looping function in mouse and human cells and that it largely functions independently of CTCF. Instead, ZNF143/ZFP143 is an essential and highly conserved transcription factor that largely binds promoters proximally, exhibits an extremely stable chromatin dwell time (>20 min), and regulates an important subset of mitochondrial and ribosomal genes. 

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5. Evolution of transcription factor binding through sequence variations and turnover of binding sites

   https://doi.org/10.1101/gr.276715.122  

   Krieger, Gat; Lupo, Offir; Wittkopp, Patricia; Barkai, Naama (June 2022, Genome Research)

   Variations in noncoding regulatory sequences play a central role in evolution. Interpreting such variations, however, remains difficult even in the context of defined attributes such as transcription factor (TF) binding sites. Here, we systematically link variations in cis -regulatory sequences to TF binding by profiling the allele-specific binding of 27 TFs expressed in a yeast hybrid, in which two related genomes are present within the same nucleus. TFs localize preferentially to sites containing their known consensus motifs but occupy only a small fraction of the motif-containing sites available within the genomes. Differential binding of TFs to the orthologous alleles was well explained by variations that alter motif sequence, whereas differences in chromatin accessibility between alleles were of little apparent effect. Motif variations that abolished binding when present in only one allele were still bound when present in both alleles, suggesting evolutionary compensation, with a potential role for sequence conservation at the motif's vicinity. At the level of the full promoter, we identify cases of binding-site turnover, in which binding sites are reciprocally gained and lost, yet most interspecific differences remained uncompensated. Our results show the flexibility of TFs to bind imprecise motifs and the fast evolution of TF binding sites between related species. 

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