Bayesian identification of candidate transcription factors for the regulation of gene expression.

Aquaporin-2 () gene transcription is strongly regulated by vasopressin in the renal collecting duct. However, the transcription factors (TFs) responsible for the regulation of expression of Aqp2 remain largely unknown. We used Bayes' theorem to integrate several -omics data sets to stratify the 1,344 TFs present in the mouse genome with regard to probabilities of regulating gene transcription. Also, we carried out new RNA sequencing experiments mapping the time course of vasopressin-induced changes in the transcriptome of mpkCCD cells to identify TFs that change in tandem with Aqp2. The analysis identified 17 of 1,344 TFs that are most likely to be involved in the regulation of gene transcription. These TFs included eight that have been proposed in prior studies to play a role in Aqp2 regulation, viz., Cebpb, Elf1, Elf3, Ets1, Jun, Junb, Nfkb1, and Sp1. The remaining nine represent new candidates for future studies (Atf1, Irf3, Klf5, Klf6, Mef2d, Nfyb, Nr2f6, Stat3, and Nr4a1). Conspicuously absent is CREB (Creb1), which has been widely proposed to mediate vasopressin-induced regulation of gene transcription (Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA. 82: 205-244, 2002; Kortenoeven ML, Fenton RA. 1840: 1533-1549, 2014; Bockenhauer D, Bichet DG. 11: 576-588, 2015; Pearce D, Soundararajan R, Trimpert C, Kashlan OB, Deen PM, Kohan DE. 10: 135-146, 2015). Instead, another CREB-like TF, Atf1, ranked fourth among all TFs. RNA sequencing time-course experiments showed a rapid increase in mRNA, within 3 h of vasopressin exposure. This response was matched by an equally rapid increase in the abundance of the mRNA coding for Cebpb, which we have shown by chromatin immunoprecipitation-sequencing studies to bind downstream from the gene. The identified TFs provide a roadmap for future studies to understand regulation of gene expression. Abetted by the advent of systems biology-based ("-omics") techniques in the 21st century, there has been a massive expansion of published data relevant to virtually every physiological question. The authors have developed a large-scale data integration approach based on the application of Bayes'' theorem. In the current work, they integrated 12 different -omics data sets to identify the transcription factors most likely to mediate vasopressin-dependent regulation of transcription of the aquaporin-2 gene.