Chatonnet, F. | bioRxiv Science

bioRxiv2021

Reproducibility and reusability limitations in Regulatory Circuits: analysis and solutions

The Regulatory Circuits project is among the most recent and the most complete attempts to identify cell-type specific regulatory networks in Human. It is one of the largest efforts of public genomics data integration, based on data from the major consortia FANTOM5, ENCODE and Roadmap Epigenomics. This project is a main provider of biological data, cited more than 224 times (Google Scholar) and its resulting networks were used in at least 42 other articles. For such a general resource, reproducibility of both the outputs (regulation networks) and methods (data integration pipeline) is a major issue, since biological data are updated regularly. In addition, users may want to introduce new data into the Regulatory Circuits framework to provide networks about previously uncharacterized cell types or to add information about specific regulators, which require to re-execute the whole pipeline on the new data. In this article, we analyze the various factors limiting reproducibility of the Regulatory Circuits data and methods. Starting from a factual description of our understanding of the methods used in Regulatory Circuits, our contribution is two-fold: we propose (1) a characterization of the different levels of reusability, reproducibility and conceptual issues in the original workflow and (2) a new implementation of the workflow ensuring its consistency with the published description and allowing for an easier reuse and reproduction of the published outputs. Both are applicable beyond the case of Regulatory Circuits.

bioinformatics↗

bioRxiv2021

Regulus, a transcriptional regulatory networks inference tool based on Semantic Web technologies

MotivationTranscriptional regulation is performed by transcription factors (TF) binding to DNA in context-dependent regulatory regions and determines the activation or inhibition of gene expression. Current methods of transcriptional regulatory networks inference, based on one or all of TF, regions and genes activity measurements require a large number of samples for ranking the candidate TF-gene regulation relations and rarely predict whether they are activations or inhibitions. We hypothesize that transcriptional regulatory networks can be inferred from fewer samples by (1) fully integrating information on TF binding, gene expression and regulatory regions accessibility, (2) reducing data complexity and (3) using biology-based logical constraints to determine the global consistency of the candidate TF-gene relations and qualify them as activations or inhibitions. ResultsWe introduce Regulus, a method which computes TF-gene relations from gene expressions, regulatory region activities and TF binding sites data, together with the genomic locations of all entities. After aggregating gene expressions and region activities into patterns, data are integrated into a RDF endpoint. A dedicated SPARQL query retrieves all potential relations between expressed TF and genes involving active regulatory regions. These TF-region-gene relations are then filtered using a logical consistency check translated from biological knowledge, also allowing to qualify them as activation or inhibition. Regulus compares favorably to the closest network inference method, provides signed relations consistent with public databases and, when applied to biological data, identifies both known and potential new regulators. Altogether, Regulus is devoted to transcriptional network inference in settings where samples are scarce and cell populations are closely related. Regulus is available at https://gitlab.com/teamDyliss/regulus

bioinformatics↗