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A mitotic transcriptional switch in polycystic kidney disease

Abstract

Hepatocyte nuclear factor-1β (HNF-1β) is a transcription factor required for the expression of several renal cystic genes and whose prenatal deletion leads to polycystic kidney disease (PKD)1. We show here that inactivation of Hnf1b from postnatal day 10 onward does not elicit cystic dilations in tubules after their proliferative morphogenetic elongation is over. Cystogenic resistance is intrinsically linked to the quiescent state of cells. In fact, when Hnf1b deficient quiescent cells are forced to proliferate by an ischemia-reperfusion injury, they give rise to cysts, owing to loss of oriented cell division. Remarkably, in quiescent cells, the transcription of crucial cystogenic target genes is maintained even in the absence of HNF-1β. However, their expression is lost as soon as cells proliferate and the chromatin of target genes acquires heterochromatin marks. These results unveil a previously undescribed aspect of gene regulation. It is well established that transcription is shut off during the mitotic condensation of chromatin2,3. We propose that transcription factors such as HNF-1β might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1β remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1β is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing.

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Figure 1: Time-restricted cystogenic competence.
Figure 2: Tubular regeneration elicits distorted cell division and dilations in Hnf1b deficiency.
Figure 3: Effect of proliferation on HNF-1β target gene expression and chromatin modifications.
Figure 4: HNF-1β behaves as a bookmarking factor.

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Acknowledgements

We are grateful to S. Bettiol, J.B. Weitzman and M. Yaniv for critical advice. We are grateful to R. Sandford (Cambridge Institute of Medical Research) for Pkd2-specific antibodies and to B. Viollet, (Institut Cochin, Paris) for the GFP–HNF-4α fusion construct. MxCre mice were kindly provided by K. Rajewsky (Harvard Medical School, Boston), and the ROSA26R strain was provided by P. Soriano (Fred Hutchinson Cancer Research Center, Seattle). We thank E. Perret and P. Roux from the “Plate-Forme d'Imagerie Dynamique,” Institut Pasteur, Paris) for assistance and advice. This work was supported by Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Polycystic Kidney Disease Foundation, Société de Néphrologie, Agence Nationale Recherche, Fondation de la Recherche Médicale. F.V. was a recipient of a fellowship from Société de Néphrologie and from Fundación La Caixa.

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Authors and Affiliations

Authors

Contributions

F.V., experimental mouse model development, X-gal staining, immunofluorescence analysis, gene expression analysis; chromatin immunoprecipitation studies, cell culture and time-lapse video microscopy. S.L.C., renal ishemia-reperfusion injury, histological studies, immunohistochemistry, mitotic angle measurements and gene expression studies. E.F., experimental design, mitotic angle measurements and experimental mouse model development. C.C., GFP fusion proteins and cell culture studies. S.G., bioinformatic analysis of genomic HNF-1 binding sites. A.D., mouse breeding and genotyping. P.I., cell line expressing dominant-negative HNF-1β. F.T. supervised the studies and wrote the paper. M.P. supervised the project and wrote the paper.

Corresponding author

Correspondence to Marco Pontoglio.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Table 1, Supplementary Data and Supplementary Methods (PDF 1683 kb)

Supplementary Video 1

Localization of HNF1β and HNF4α GFP fusion proteins during mitosis. Contrary to the vast majority of transcription factors (exemplified here by HNF4α) HNF1β remains associated with the chromatin during mitosis. (To play, view as slideshow.) (PPT 10368 kb)

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Verdeguer, F., Le Corre, S., Fischer, E. et al. A mitotic transcriptional switch in polycystic kidney disease. Nat Med 16, 106–110 (2010). https://doi.org/10.1038/nm.2068

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