HNF1B Alters an Evolutionarily Conserved Nephrogenic Program of Target Genes

Background:Hepatocyte nuclear factor 1-beta (HNF1B) is an essential transcription factor during embryogenesis. Mutations inHNF1Bare the most common monogenic causes of congenital cystic dysplastic renal malformations. The direct functional consequences of mutations inHNF1Bon its transcriptional activity are unknown.Methods:Direct reprogramming of mouse fibroblasts to induced renal tubular epithelial cells (iRECs) was conducted both with wild typeHNF1Band with patient mutations.HNF1Bwas expressed inXenopusectodermal explants. Transcriptomic analysis by bulk RNA-Seq identified conserved targets with differentially regulated expression by the wild type or theR295C mutant. CRISPR genome editing inXenopusembryos evaluated transcriptional targetsin vivo.Results:HNF1B is essential for reprogramming mouse fibroblasts to iRECs and induces development of ectopic renal organoids from pluripotentXenopuscells. The mutation R295C retains reprogramming and inductive capacity but alters the expression of specific sets of downstream target genes, instead of diminishing overall transcriptional activity of HNF1B. Surprisingly, targets associated with polycystic kidney disease were less affected than genes affected in congenital renal anomalies. Cross-species conserved transcriptional targets were dysregulated in hnf1b CRISPR-depleted Xenopus embryos, confirming their dependence onhnf1b.Conclusions:HNF1B activates an evolutionarily conserved program of target genes that disease-causing mutations selectively disrupt. These findings provide insights into the renal transcriptional network that controls nephrogenesis.