Summary The synthesis of Type I collagen, the main component of the bone matrix, precedes the expression of Runx2, the earliest determinant of osteoblast differentiation. We hypothesized that the osteoblast's energetic needs might explain this apparent paradox. We show here that glucose, the main nutrient of osteoblasts, is transported in these cells through Glut1 whose expression precedes that of Runx2. Glucose uptake favors osteoblast differentiation by suppressing the AMPK-dependent proteasomal degradation of Runx2 and promotes bone formation by inhibiting another function of AMPK. While Runx2 cannot induce osteoblast differentiation when glucose uptake is compromised, raising blood glucose levels restores collagen synthesis in Runx2-null osteoblasts and initiates bone formation in Runx2-deficient embryos. Moreover, Runx2 favors Glut1 expression, and this feed-forward regulation between Runx2 and Glut1 determines the onset of osteoblast differentiation during development and the extent of bone formation throughout life. These results reveal an unexpected intricacy between bone and glucose metabolism.

In the originally published author list, we inadvertently misspelled Takashi Iezaki's surname. The author list has been corrected online.

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.