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HNF1B alters an evolutionarily conserved nephrogenic program of target genes

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Item Type:Article
Title:HNF1B alters an evolutionarily conserved nephrogenic program of target genes
Creators Name:Grand, K. and Stoltz, M. and Rizzo, L. and Röck, R. and Kaminski, M.M. and Salinas, G. and Getwan, M. and Naert, T. and Pichler, R. and Lienkamp, S.S.
Abstract:BACKGROUND: Hepatocyte nuclear factor 1-beta (HNF1B) is an essential transcription factor during embryogenesis. Mutations in HNF1B are the most common monogenic causes of congenital cystic dysplastic renal malformations. The direct functional consequences of mutations in HNF1B on its transcriptional activity are unknown. METHODS: Direct reprogramming of mouse fibroblasts to induced renal tubular epithelial cells (iRECs) was conducted both with wild type HNF1B and with patient mutations. HNF1B was expressed in Xenopus 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 Xenopus embryos evaluated transcriptional targets in vivo. RESULTS: HNF1B is essential for reprogramming mouse fibroblasts to iRECs and induces development of ectopic renal organoids from pluripotent Xenopus 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 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.
Keywords:HNF1B, Genetic Renal Disease, Direct Reprogramming, Kidney Development, Transcription Regulation, Animals, Xenopus laevis, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:412-432
Date:March 2023
Official Publication:https://doi.org/10.1681/ASN.2022010076
PubMed:View item in PubMed

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