Human mutations affect the epigenetic/bookmarking function of HNF1B.

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. HNF1? is a bookmarking transcription factor that is frequently mutated in patients suffering from renal multicystic dysplasia and diabetes. Here, we show that HNF1? bookmarking activity is impaired by naturally occurring mutations found in patients. Interestingly, this defect in HNF1? 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 HNF1? mutants. Furthermore, we demonstrate that importin-? is involved in the maintenance of the mitotic retention of HNF1?, 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 HNF1?, a bookmarking factor that plays crucial roles in the epigenetic transmission of information through the cell cycle.

SUBMITTER: Lerner J 

PROVIDER: S-EPMC5041451 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature