A mitotic transcriptional switch in polycystic kidney disease

Francisco Verdeguer, Stephanie Le Corre, Evelyne Fischer, Celine Callens, Serge Garbay, Antonia Doyen, Peter Igarashi, Fabiola Terzi, Marco Pontoglio

Research output: Contribution to journalArticle

102 Scopus citations

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). 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 languageEnglish (US)
Pages (from-to)106-110
Number of pages5
JournalNature medicine
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Verdeguer, F., Le Corre, S., Fischer, E., Callens, C., Garbay, S., Doyen, A., Igarashi, P., Terzi, F., & Pontoglio, M. (2010). A mitotic transcriptional switch in polycystic kidney disease. Nature medicine, 16(1), 106-110. https://doi.org/10.1038/nm.2068