RegulonDB version 9.0: high-level integration of gene regulation, coexpression, motif clustering and beyond.

RegulonDB (http://regulondb.ccg.unam.mx) is one of the most useful and important resources on bacterial gene regulation,as it integrates the scattered scientific knowledge of the best-characterized organism, Escherichia coli K-12, in a database that organizes large amounts of data. Its electronic format enables researchers to compare their results with the legacy of previous knowledge and supports bioinformatics tools and model building. Here, we summarize our progress with RegulonDB since our last Nucleic Acids Research publication describing RegulonDB, in 2013. In addition to maintaining curation up-to-date, we report a collection of 232 interactions with small RNAs affecting 192 genes, and the complete repertoire of 189 Elementary Genetic Sensory-Response units (GENSOR units), integrating the signal, regulatory interactions, and metabolic pathways they govern. These additions represent major progress to a higher level of understanding of regulated processes. We have updated the computationally predicted transcription factors, which total 304 (184 with experimental evidence and 120 from computational predictions); we updated our position-weight matrices and have included tools for clustering them in evolutionary families. We describe our semiautomatic strategy to accelerate curation, including datasets from high-throughput experiments, a novel coexpression distance to search for 'neighborhood' genes to known operons and regulons, and computational developments.

RegulonDB v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more.

This article summarizes our progress with RegulonDB (http://regulondb.ccg.unam.mx/) during the past 2 years. We have kept up-to-date the knowledge from the published literature regarding transcriptional regulation in Escherichia coli K-12. We have maintained and expanded our curation efforts to improve the breadth and quality of the encoded experimental knowledge, and we have implemented criteria for the quality of our computational predictions. Regulatory phrases now provide high-level descriptions of regulatory regions. We expanded the assignment of quality to various sources of evidence, particularly for knowledge generated through high-throughput (HT) technology. Based on our analysis of most relevant methods, we defined rules for determining the quality of evidence when multiple independent sources support an entry. With this latest release of RegulonDB, we present a new highly reliable larger collection of transcription start sites, a result of our experimental HT genome-wide efforts. These improvements, together with several novel enhancements (the tracks display, uploading format and curational guidelines), address the challenges of incorporating HT-generated knowledge into RegulonDB. Information on the evolutionary conservation of regulatory elements is also available now. Altogether, RegulonDB version 8.0 is a much better home for integrating knowledge on gene regulation from the sources of information currently available.

RegulonDB version 7.0: transcriptional regulation of Escherichia coli K-12 integrated within genetic sensory response units (Gensor Units).

RegulonDB (http://regulondb.ccg.unam.mx/) is the primary reference database of the best-known regulatory network of any free-living organism, that of Escherichia coli K-12. The major conceptual change since 3 years ago is an expanded biological context so that transcriptional regulation is now part of a unit that initiates with the signal and continues with the signal transduction to the core of regulation, modifying expression of the affected target genes responsible for the response. We call these genetic sensory response units, or Gensor Units. We have initiated their high-level curation, with graphic maps and superreactions with links to other databases. Additional connectivity uses expandable submaps. RegulonDB has summaries for every transcription factor (TF) and TF-binding sites with internal symmetry. Several DNA-binding motifs and their sizes have been redefined and relocated. In addition to data from the literature, we have incorporated our own information on transcription start sites (TSSs) and transcriptional units (TUs), obtained by using high-throughput whole-genome sequencing technologies. A new portable drawing tool for genomic features is also now available, as well as new ways to download the data, including web services, files for several relational database manager systems and text files including BioPAX format.

Assisted curation of regulatory interactions and growth conditions of OxyR in E. coli K-12.

Given the current explosion of data within original publications generated in the field of genomics, a recognized bottleneck is the transfer of such knowledge into comprehensive databases. We have for years organized knowledge on transcriptional regulation reported in the original literature of Escherichia coli K-12 into RegulonDB (http://regulondb.ccg.unam.mx), our database that is currently supported by >5000 papers. Here, we report a first step towards the automatic biocuration of growth conditions in this corpus. Using the OntoGene text-mining system (http://www.ontogene.org), we extracted and manually validated regulatory interactions and growth conditions in a new approach based on filters that enable the curator to select informative sentences from preprocessed full papers. Based on a set of 48 papers dealing with oxidative stress by OxyR, we were able to retrieve 100% of the OxyR regulatory interactions present in RegulonDB, including the transcription factors and their effect on target genes. Our strategy was designed to extract, as we did, their growth conditions. This result provides a proof of concept for a more direct and efficient curation process, and enables us to define the strategy of the subsequent steps to be implemented for a semi-automatic curation of original literature dealing with regulation of gene expression in bacteria. This project will enhance the efficiency and quality of the curation of knowledge present in the literature of gene regulation, and contribute to a significant increase in the encoding of the regulatory network of E. coli. RegulonDB Database URL: http://regulondb.ccg.unam.mx OntoGene URL: http://www.ontogene.org.

Extracting regulatory networks of Escherichia coli from RegulonDB.

RegulonDB contains the largest and currently best-known data set on transcriptional regulation in a single free-living organism, that of Escherichia coli K-12 (Gama-Castro et al. Nucleic Acids Res 36:D120-D124, 2008). This organized knowledge has been the gold standard for the implementation of bioinformatic predictive methods on gene regulation in bacteria (Collado-Vides et al. J Bacteriol 191:23-31, 2009). Given the complexity of different types of interactions, the difficulty of visualizing in a single figure of the whole network, and the different uses of this knowledge, we are making available different views of the genetic network. This chapter describes case studies about how to access these views, via precomputed files, web services and SQL, including sigma-gene relationships corresponding to transcription of alternative RNA polymerase holoenzyme promoters; as well as, transcription factor (TF)-genes, TF-operons, TF-TF, and TF-regulon interactions. 17.

The BioPAX community standard for pathway data sharing.

Biological Pathway Exchange (BioPAX) is a standard language to represent biological pathways at the molecular and cellular level and to facilitate the exchange of pathway data. The rapid growth of the volume of pathway data has spurred the development of databases and computational tools to aid interpretation; however, use of these data is hampered by the current fragmentation of pathway information across many databases with incompatible formats. BioPAX, which was created through a community process, solves this problem by making pathway data substantially easier to collect, index, interpret and share. BioPAX can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. Using BioPAX, millions of interactions, organized into thousands of pathways, from many organisms are available from a growing number of databases. This large amount of pathway data in a computable form will support visualization, analysis and biological discovery.