Characterizing the regulatory logic of transcriptional control at the DNA sequence level by ensembles of thermodynamic models.

motivationUnderstanding how the genome encodes the regulatory logic of transcription is a main challenge of the post-genomic era, and can be overcome with the aid of customized computational tools.

resultsWe report an automated framework for analyzing an ensemble of fits to data of a thermodynamics-based sequence-level model for transcriptional regulation. The fits are clustered accordingly with their intrinsic regulatory logic. A multiscale analysis enables visualization of quantitative features resulting from the deconvolution of the regulatory profile provided by multiple transcription factors interacting with the locus of a gene. Quantitative experimental data on reporters driven by the whole locus of the even-skipped gene in the blastoderm of Drosophila embryos was used for validating our approach. A few clusters of highly active DNA binding sites within the enhancers collectively modulate even-skipped gene transcription. Analysis of variable enhancers' length shows the importance of bound protein-protein interactions for transcriptional regulation. The interplay between activation and quenching enables function conservation of enhancers despite length variations. AVAILABILITY AND IMPLEMENTATION: The transcription factor level data used for performing the reported study is accessible in the input files in Zenodo and GitHub as well the full code. Additional data from formerly FlyEx database will be available under request.