Data integration has become a useful strategy for uncovering new insights into complex biological networks. Researchers at the German Rheumatism Research Center studied whether this approach can help to delineate the signal transducer and activator of transcription 6 (STAT6)-mediated transcriptional network driving T helper (Th) 2 cell fate decisions. To this end, we performed an integrative analysis of publicly available RNA-seq data of Stat6-knockout mouse studies together with STAT6 ChIP-seq data and their own gene expression time series data during Th2 cell differentiation. The researchers focused on transcription factors (TFs), cytokines, and cytokine receptors and delineated 59 positively and 41 negatively STAT6-regulated genes, which were used to construct a transcriptional network around STAT6. The network illustrates that important and well-known TFs for Th2 cell differentiation are positively regulated by STAT6 and act either as activators for Th2 cells (e.g., Gata3, Atf3, Satb1, Nfil3, Maf, and Pparg) or as suppressors for other Th cell subpopulations such as Th1 (e.g., Ar), Th17 (e.g., Etv6), or iTreg (e.g., Stat3 and Hif1a) cells. Moreover, this approach reveals 11 TFs (e.g., Atf5, Creb3l2, and Asb2) with unknown functions in Th cell differentiation. This fact together with the observed enrichment of asthma risk genes among those regulated by STAT6 underlines the potential value of the data integration strategy used here. Thus, these results clearly support the opinion that data integration is a useful tool to delineate complex physiological processes.
Strategy of data integration
A. Workflow for the construction of the STAT6 network. The filter criteria and datasets used for each step are shown in the first row and highlighted in different colors. The filter criteria and/ or the number of genes are listed for each integration step and gene group in the second row. B. The Venn diagram shows the three datasets forming the basic network. The intersection (100 genes, highlighted bold) of STAT6- regulated genes (green) with TFs, cytokines, and cytokine receptors (purple) are dissected into direct and indirect target genes of STAT6 by integrating the STAT6 ChIP-seq data (orange).