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HNF1B Alters an Evolutionarily Conserved Nephrogenic Program of Target Genes.
Grand, Kelli; Stoltz, Martine; Rizzo, Ludovica; Röck, Ruth; Kaminski, Michael M; Salinas, Gabriela; Getwan, Maike; Naert, Thomas; Pichler, Roman; Lienkamp, Soeren S.
Afiliação
  • Grand K; Institute of Anatomy, University of Zurich, Zurich, Switzerland.
  • Stoltz M; The University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Rizzo L; Institute of Anatomy, University of Zurich, Zurich, Switzerland.
  • Röck R; Institute of Anatomy, University of Zurich, Zurich, Switzerland.
  • Kaminski MM; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Salinas G; Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.
  • Getwan M; Berlin Institute of Health, Berlin, Germany.
  • Naert T; Berlin Institute of Health, Berlin, Germany.
  • Pichler R; Institute of Anatomy, University of Zurich, Zurich, Switzerland.
  • Lienkamp SS; Institute of Anatomy, University of Zurich, Zurich, Switzerland.
J Am Soc Nephrol ; 34(3): 412-432, 2023 03 01.
Article em En | MEDLINE | ID: mdl-36522156
SIGNIFICANCE STATEMENT: Mutations in hepatocyte nuclear factor-1 ß ( HNF1B ) are the most common monogenic causes of congenital renal malformations. HNF1B is necessary to directly reprogram fibroblasts to induced renal tubule epithelial cells (iRECs) and, as we demonstrate, can induce ectopic pronephric tissue in Xenopus ectodermal organoids. Using these two systems, we analyzed the effect of HNF1B mutations found in patients with cystic dysplastic kidney disease. We found cross-species conserved targets of HNF1B, identified transcripts that are differentially regulated by the patient-specific mutant protein, and functionally validated novel HNF1B targets in vivo . These results highlight evolutionarily conserved transcriptional mechanisms and provide insights into the genetic circuitry of nephrogenesis. BACKGROUND: Hepatocyte nuclear factor-1 ß (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 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 R295C mutant. CRISPR/Cas9 genome editing in Xenopus embryos evaluated transcriptional targets in vivo . RESULTS: HNF1B is essential for reprogramming mouse fibroblasts to induced renal tubular epithelial cells 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Renais Císticas / Fator 1-beta Nuclear de Hepatócito Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Am Soc Nephrol Assunto da revista: NEFROLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Renais Císticas / Fator 1-beta Nuclear de Hepatócito Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Am Soc Nephrol Assunto da revista: NEFROLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suíça