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XB-ART-59464
Sci Rep 2022 Nov 19;121:19921. doi: 10.1038/s41598-022-21171-x.
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Hnf1b renal expression directed by a distal enhancer responsive to Pax8.

Goea L , Buisson I , Bello V , Eschstruth A , Paces-Fessy M , Le Bouffant R , Chesneau A , Cereghini S , Riou JF , Umbhauer M .


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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.

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Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: dll1 emx2 hnf1b hnf4a irx1 irx2 irx3 lhx1 mmut osr2 pax2 pax8 slc45a2 tpo
GO keywords: kidney development [+]
Lines/Strains: ???displayArticle.morpholinos??? pax2 MO2 pax2 MO3 pax8 MO1 pax8 MO2
gRNAs referenced: slc45a2 gRNA6 slc45a2 gRNA7

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Phenotypes: Xtr Wt + pax8 MO (Fig. 5a c2r3)

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References [+] :
Abraham, The Groucho-associated phosphatase PPM1B displaces Pax transactivation domain interacting protein (PTIP) to switch the transcription factor Pax2 from a transcriptional activator to a repressor. 2015, Pubmed