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Nucleic Acids Res. 2016 Sep 30;44(17):8097-111. doi: 10.1093/nar/gkw467. Epub 2016 May 26.

Human mutations affect the epigenetic/bookmarking function of HNF1B.

Author information

1
Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016/CNRS UMR 8104/Université Paris-Descartes, Paris 75014, France.
2
Department of Pediatric Nephrology, Assistance Publique des Hôpitaux de Paris, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Hospital Necker-Enfants Malades, Paris 75015, France.
3
Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016/CNRS UMR 8104/Université Paris-Descartes, Paris 75014, France marco.pontoglio@inserm.fr.

Abstract

Bookmarking factors are transcriptional regulators involved in the mitotic transmission of epigenetic information via their ability to remain associated with mitotic chromatin. The mechanisms through which bookmarking factors bind to mitotic chromatin remain poorly understood. HNF1β is a bookmarking transcription factor that is frequently mutated in patients suffering from renal multicystic dysplasia and diabetes. Here, we show that HNF1β bookmarking activity is impaired by naturally occurring mutations found in patients. Interestingly, this defect in HNF1β mitotic chromatin association is rescued by an abrupt decrease in temperature. The rapid relocalization to mitotic chromatin is reversible and driven by a specific switch in DNA-binding ability of HNF1β mutants. Furthermore, we demonstrate that importin-β is involved in the maintenance of the mitotic retention of HNF1β, suggesting a functional link between the nuclear import system and the mitotic localization/translocation of bookmarking factors. Altogether, our studies have disclosed novel aspects on the mechanisms and the genetic programs that account for the mitotic association of HNF1β, a bookmarking factor that plays crucial roles in the epigenetic transmission of information through the cell cycle.

PMID:
27229139
PMCID:
PMC5041451
DOI:
10.1093/nar/gkw467
[Indexed for MEDLINE]
Free PMC Article

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