Integration of chromosome locations and functional aspects of enhancers and topologically associating domains in knowledge graphs enables versatile queries about gene regulation.

Knowledge about transcription factor binding and regulation, target genes, cis-regulatory modules and topologically associating domains is not only defined by functional associations like biological processes or diseases but also has a determinative genome location aspect. Here, we exploit these location and functional aspects together to develop new strategies to enable advanced data querying. Many databases have been developed to provide information about enhancers, but a schema that allows the standardized representation of data, securing interoperability between resources, has been lacking. In this work, we use knowledge graphs for the standardized representation of enhancers and topologically associating domains, together with data about their target genes, transcription factors, location on the human genome, and functional data about diseases and gene ontology annotations. We used this schema to integrate twenty-five enhancer datasets and two domain datasets, creating the most powerful integrative resource in this field to date. The knowledge graphs have been implemented using the Resource Description Framework and integrated within the open-access BioGateway knowledge network, generating a resource that contains an interoperable set of knowledge graphs (enhancers, TADs, genes, proteins, diseases, GO terms, and interactions between domains). We show how advanced queries, which combine functional and location restrictions, can be used to develop new hypotheses about functional aspects of gene expression regulation.

Analysis of the landscape of human enhancer sequences in biological databases.

The process of gene regulation extends as a network in which both genetic sequences and proteins are involved. The levels of regulation and the mechanisms involved are multiple. Transcription is the main control mechanism for most genes, being the downstream steps responsible for refining the transcription patterns. In turn, gene transcription is mainly controlled by regulatory events that occur at promoters and enhancers. Several studies are focused on analyzing the contribution of enhancers in the development of diseases and their possible use as therapeutic targets. The study of regulatory elements has advanced rapidly in recent years with the development and use of next generation sequencing techniques. All this information has generated a large volume of information that has been transferred to a growing number of public repositories that store this information. In this article, we analyze the content of those public repositories that contain information about human enhancers with the aim of detecting whether the knowledge generated by scientific research is contained in those databases in a way that could be computationally exploited. The analysis will be based on three main aspects identified in the literature: types of enhancers, type of evidence about the enhancers, and methods for detecting enhancer-promoter interactions. Our results show that no single database facilitates the optimal exploitation of enhancer data, most types of enhancers are not represented in the databases and there is need for a standardized model for enhancers. We have identified major gaps and challenges for the computational exploitation of enhancer data.