Transcription factors (TFs) are major trans-acting factors in transcriptional regulation. Therefore, elucidating TF–target interactions is a key step toward understanding the regulatory circuitry underlying complex traits such as human diseases. We previously published a reference TF–target interaction database for humans—TRRUST (Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining)—which was constructed using sentence-based text mining, followed by manual curation. Here, we present TRRUST v2 (www.grnpedia.org/trrust) with a significant improvement from the previous version, including a significantly increased size of the database consisting of 8444 regulatory interactions for 800 TFs in humans. More importantly, TRRUST v2 also contains a database for TF–target interactions in mice, including 6552 TF–target interactions for 828 mouse TFs. TRRUST v2 is also substantially more comprehensive and less biased than other TF–target interaction databases. We also improved the web interface, which now enables prioritization of key TFs for a physiological condition depicted by a set of user-input transcriptional responsive genes. With the significant expansion in the database size and inclusion of the new web tool for TF prioritization, we believe that TRRUST v2 will be a versatile database for the study of the transcriptional regulation involved in human diseases.

The reconstruction of transcriptional regulatory networks (TRNs) is a long-standing challenge in human genetics. Numerous computational methods have been developed to infer regulatory interactions between human transcriptional factors (TFs) and target genes from high-throughput data, and their performance evaluation requires gold-standard interactions. Here we present a database of literature-curated human TF-target interactions, TRRUST (transcriptional regulatory relationships unravelled by sentence-based text-mining, http://www.grnpedia.org/trrust), which currently contains 8,015 interactions between 748 TF genes and 1,975 non-TF genes. A sentence-based text-mining approach was employed for efficient manual curation of regulatory interactions from approximately 20 million Medline abstracts. To the best of our knowledge, TRRUST is the largest publicly available database of literature-curated human TF-target interactions to date. TRRUST also has several useful features: i) information about the mode-of-regulation; ii) tests for target modularity of a query TF; iii) tests for TF cooperativity of a query target; iv) inferences about cooperating TFs of a query TF; and v) prioritizing associated pathways and diseases with a query TF. We observed high enrichment of TF-target pairs in TRRUST for top-scored interactions inferred from high-throughput data, which suggests that TRRUST provides a reliable benchmark for the computational reconstruction of human TRNs.

SummaryDisorders of the biliary epithelium, known as cholangiopathies, cause severe and irreversible liver diseases. The limited accessibility of bile duct precludes modeling of several cholangiocyte-mediated diseases. Therefore, novel approaches for obtaining functional cholangiocytes with high purity are needed. Previous work has shown that the combination of Hnf1β and Foxa3 could directly convert mouse fibroblasts into bipotential hepatic stem cell-like cells, termed iHepSCs. However, the efficiency of converting fibroblasts into iHepSCs is low, and these iHepSCs exhibit extremely low differentiation potential into cholangiocytes, thus hindering the translation of iHepSCs to the clinic. Here, we describe that the expression of Hnf1α and Foxa3 dramatically facilitates the robust generation of iHepSCs. Notably, prolonged in vitro culture of Hnf1α- and Foxa3-derived iHepSCs induces a Notch signaling-mediated secondary conversion into cholangiocyte progenitor-like cells that display dramatically enhanced differentiation capacity into mature cholangiocytes. Our study provides a robust two-step approach for obtaining cholangiocyte progenitor-like cells using defined factors.

Motivation Owing to advanced DNA sequencing and genome assembly technology, the number of species with sequenced genomes is rapidly increasing. The aim of the recently launched Earth BioGenome Project is to sequence genomes of all eukaryotic species on Earth over the next 10 years, making it feasible to obtain genomic blueprints of the majority of animal and plant species by this time. Genetic models of the sequenced species will later be subject to functional annotation, and a comprehensive molecular network should facilitate functional analysis of individual genes and pathways. However, network databases are lagging behind genome sequencing projects as even the largest network database provides gene networks for less than 10% of sequenced eukaryotic genomes, and the knowledge gap between genomes and interactomes continues to widen. Results We present BiomeNet, a database of 95 scored networks comprising over 8 million co-functional links, which can build and analyze gene networks for any species with the sequenced genome. BiomeNet transfers functional interactions between orthologous proteins from source networks to the target species within minutes and automatically constructs gene networks with the quality comparable to that of existing networks. BiomeNet enables assembly of the first-in-species gene networks not available through other databases, which are highly predictive of diverse biological processes and can also provide network analysis by extracting subnetworks for individual biological processes and network-based gene prioritizations. These data indicate that BiomeNet could enhance the benefits of decoding the genomes of various species, thus improving our understanding of the Earth’ biodiversity. Availability and implementation The BiomeNet is freely available at http://kobic.re.kr/biomenet/. Supplementary information Supplementary data are available at Bioinformatics online.