Objective: Portal mesenchymal cells induces the epithelial differentiation of the bile ducts in the developing liver via one of the Delta-Notch signaling components, JAGGED1. Although this differential induction is crucial for normal liver physiology as its genetic disorder (Alagille syndrome) causes jaundice, the molecular mechanism behind JAGGED1 expression remain unknown. Here, we searched for upstream regulatory transcription factors of JAGGED1 using an integrated bioinformatics method.
Results: According to DoRothEA database, which integrated multiple lines of evidence on the relation between transcription factors and its downstream target genes, three transcription factors were predicted to be upstream of JAGGED1: SLUG, SOX2 and EGR1. Among these, SLUG and EGR1 were enriched in ACTA2 expressing portal mesenchymal cells in the previously reported two human fetal liver single cell RNA-seq data. JAGGED1 expressing portal mesenchymal cells tended to express of SLUG rather than EGR1, supporting that SLUG induced JAGGED1 expression. Together with the higher confidentiality of SLUG (DoRothEA level A) over EGR1 (DoRothEA level D), we concluded that SLUG was one of the most important candidate transcription factors upstream of JAGGED1. These results would add mechanistic insights into developmental biology on how portal mesenchymal cells supports biliary development in the liver.