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). 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 chromatin. 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.
|Original language||English (US)|
|Number of pages||5|
|State||Published - Jan 2010|
Bibliographical noteFunding Information:
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.