A mitotic transcriptional switch in polycystic kidney disease.
Hepatocyte nuclear factor-1beta (HNF-1beta) 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-1beta. 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-1beta might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1beta remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1beta is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing.
Verdeguer
Francisco
F
Gene Expression, Development and Disease Laboratory, Developmental Biology Department, Institut Pasteur, Paris, France.
Le Corre
Stephanie
S
Fischer
Evelyne
E
Callens
Celine
C
Garbay
Serge
S
Doyen
Antonia
A
Igarashi
Peter
P
Terzi
Fabiola
F
Pontoglio
Marco
M
D000818:Animals; D002455:Cell Division / Q000235:genetics; D002843:Chromatin / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000502:physiology*; D007684:Kidney Tubules / Q000254:growth & development; D051379:Mice; D008938:Mitosis / Q000502:physiology; D007690:Polycystic Kidney Diseases / Q000209:etiology / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics / Q000528:radiation effects
D002843:Chromatin; C496496:Hnf1b protein, mouse; D051539:Hepatocyte Nuclear Factor 1-beta