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BMI1 represses Ink4a/Arf and Hox genes to regulate stem cells in the rodent incisor

Abstract

The polycomb group gene Bmi1 is required for maintenance of adult stem cells in many organs1,2. Inactivation of Bmi1 leads to impaired stem cell self-renewal due to deregulated gene expression. One critical target of BMI1 is Ink4a/Arf, which encodes the cell-cycle inhibitors p16Ink4a and p19Arf (ref. 3). However, deletion of Ink4a/Arf only partially rescues Bmi1-null phenotypes4, indicating that other important targets of BMI1 exist. Here, using the continuously growing mouse incisor as a model system, we report that Bmi1 is expressed by incisor stem cells and that deletion of Bmi1 resulted in fewer stem cells, perturbed gene expression and defective enamel production. Transcriptional profiling revealed that Hox expression is normally repressed by BMI1 in the adult, and functional assays demonstrated that BMI1-mediated repression of Hox genes preserves the undifferentiated state of stem cells. As Hox gene upregulation has also been reported in other systems when Bmi1 is inactivated1,2,5,6,7, our findings point to a general mechanism whereby BMI1-mediated repression of Hox genes is required for the maintenance of adult stem cells and for prevention of inappropriate differentiation.

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Figure 1: Bmi1-expressing cells in the dental epithelium are stem cells.
Figure 2: Deletion of Bmi1 affects adult LaCL through both Ink4a/Arf-dependent and -independent mechanisms.
Figure 3: Bmi1 suppresses expression of Ink4a/Arf and Hox genes.
Figure 4: Hox gene upregulation contributes to the Bmi1 loss-of-function phenotype.
Figure 5: Overexpression of Hoxc9 in LaCLs phenocopies Bmi1 mutants.

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Acknowledgements

We thank members of the Klein laboratory for helpful advice, F. Michon for discussion, D-K. Tran and S. Alto for technical assistance, X-P. Wang for help with the culture system, A. Barczak and the UCSF Microarray Core Facilities for help with experiments and analysis, and Irving Weissman for mice. This work was supported by R01-DE021420 (NIH/NIDCR) and a CIRM New Faculty Award II, both to O.D.K.

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B.B., J.K-H.H., N.B.S., H.J., E.S., R-P.H., A.F.G., J.S.D and O.D.K. designed and performed experiments. B.B., J.K-H.H and O.D.K. wrote the manuscript. All authors discussed results, analysed data and edited the manuscript.

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Correspondence to Ophir D. Klein.

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Biehs, B., Hu, JH., Strauli, N. et al. BMI1 represses Ink4a/Arf and Hox genes to regulate stem cells in the rodent incisor. Nat Cell Biol 15, 846–852 (2013). https://doi.org/10.1038/ncb2766

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