A multi-scale expression and regulation knowledge base for Escherichia coli.

Transcriptomic data is accumulating rapidly; thus, scalable methods for extracting knowledge from this data are critical. Here, we assembled a top-down expression and regulation knowledge base for Escherichia coli. The expression component is a 1035-sample, high-quality RNA-seq compendium consisting of data generated in our lab using a single experimental protocol. The compendium contains diverse growth conditions, including: 9 media; 39 supplements, including antibiotics; 42 heterologous proteins; and 76 gene knockouts. Using this resource, we elucidated global expression patterns. We used machine learning to extract 201 modules that account for 86% of known regulatory interactions, creating the regulatory component. With these modules, we identified two novel regulons and quantified systems-level regulatory responses. We also integrated 1675 curated, publicly-available transcriptomes into the resource. We demonstrated workflows for analyzing new data against this knowledge base via deconstruction of regulation during aerobic transition. This resource illuminates the E. coli transcriptome at scale and provides a blueprint for top-down transcriptomic analysis of non-model organisms.

Optimal dimensionality selection for independent component analysis of transcriptomic data.

BACKGROUND: Independent component analysis is an unsupervised machine learning algorithm that separates a set of mixed signals into a set of statistically independent source signals. Applied to high-quality gene expression datasets, independent component analysis effectively reveals both the source signals of the transcriptome as co-regulated gene sets, and the activity levels of the underlying regulators across diverse experimental conditions. Two major variables that affect the final gene sets are the diversity of the expression profiles contained in the underlying data, and the user-defined number of independent components, or dimensionality, to compute. Availability of high-quality transcriptomic datasets has grown exponentially as high-throughput technologies have advanced; however, optimal dimensionality selection remains an open question. METHODS: We computed independent components across a range of dimensionalities for four gene expression datasets with varying dimensions (both in terms of number of genes and number of samples). We computed the correlation between independent components across different dimensionalities to understand how the overall structure evolves as the number of user-defined components increases. We then measured how well the resulting gene clusters reflected known regulatory mechanisms, and developed a set of metrics to assess the accuracy of the decomposition at a given dimension. RESULTS: We found that over-decomposition results in many independent components dominated by a single gene, whereas under-decomposition results in independent components that poorly capture the known regulatory structure. From these results, we developed a new method, called OptICA, for finding the optimal dimensionality that controls for both over- and under-decomposition. Specifically, OptICA selects the highest dimension that produces a low number of components that are dominated by a single gene. We show that OptICA outperforms two previously proposed methods for selecting the number of independent components across four transcriptomic databases of varying sizes. CONCLUSIONS: OptICA avoids both over-decomposition and under-decomposition of transcriptomic datasets resulting in the best representation of the organism's underlying transcriptional regulatory network.

BiGG Models 2020: multi-strain genome-scale models and expansion across the phylogenetic tree.

The BiGG Models knowledge base (http://bigg.ucsd.edu) is a centralized repository for high-quality genome-scale metabolic models. For the past 12 years, the website has allowed users to browse and search metabolic models. Within this update, we detail new content and features in the repository, continuing the original effort to connect each model to genome annotations and external databases as well as standardization of reactions and metabolites. We describe the addition of 31 new models that expand the portion of the phylogenetic tree covered by BiGG Models. We also describe new functionality for hosting multi-strain models, which have proven to be insightful in a variety of studies centered on comparisons of related strains. Finally, the models in the knowledge base have been benchmarked using Memote, a new community-developed validator for genome-scale models to demonstrate the improving quality and transparency of model content in BiGG Models.