HNF1B Alters an Evolutionarily Conserved Nephrogenic Program of Target Genes.
Journal of the American Society of Nephrology : JASN(2022)
Abstract
Hepatocyte nuclear factor 1-beta (HNF1B) is an essential transcription factor during embryogenesis. Mutations in are the most common monogenic causes of congenital cystic dysplastic renal malformations. The direct functional consequences of mutations in on its transcriptional activity are unknown. Direct reprogramming of mouse fibroblasts to induced renal tubular epithelial cells (iRECs) was conducted both with wild type and with patient mutations. was expressed in ectodermal explants. Transcriptomic analysis by bulk RNA-Seq identified conserved targets with differentially regulated expression by the wild type or theR295C mutant. CRISPR genome editing in embryos evaluated transcriptional targets HNF1B is essential for reprogramming mouse fibroblasts to iRECs and induces development of ectopic renal organoids from pluripotent cells. 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 on 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.
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Key words
HNF1B,genetic renal disease,Xenopus,direct reprogramming,kidney development,transcription regulation
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