Hnf1b renal expression directed by a distal enhancer responsive to Pax8.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 11 2022
19 11 2022
Historique:
received:
24
05
2022
accepted:
23
09
2022
entrez:
19
11
2022
pubmed:
20
11
2022
medline:
23
11
2022
Statut:
epublish
Résumé
Xenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.
Identifiants
pubmed: 36402859
doi: 10.1038/s41598-022-21171-x
pii: 10.1038/s41598-022-21171-x
pmc: PMC9675860
doi:
Substances chimiques
Hepatocyte Nuclear Factor 1-beta
138674-15-4
PAX8 protein, human
0
PAX8 Transcription Factor
0
HNF1B protein, human
0
Hnf1b protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
19921Subventions
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : MSCA-ITN-2014-642937
Informations de copyright
© 2022. The Author(s).
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