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The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions

Abstract

Embryonic development is tightly controlled. The clustered genes of the Hox family of homeobox proteins play an important part in regulating this development and also proliferation. They specify embryonic structures along the body axis, and are associated with normal and malignant cell growth1,2,3,4. The cell-cycle regulator geminin controls replication by binding to the licensing factor Cdt1, and is involved in neural differentiation5,6,7. Here, we show that murine geminin associates transiently with members of the Hox-repressing polycomb complex, with the chromatin of Hox regulatory DNA elements and with Hox proteins. Gain- and loss-of-function experiments in the chick neural tube demonstrate that geminin modulates the anterior boundary of Hoxb9 transcription, which suggests a polycomb-like activity for geminin. The interaction between geminin and Hox proteins prevents Hox proteins from binding to DNA, inhibits Hox-dependent transcriptional activation of reporter and endogenous downstream target genes, and displaces Cdt1 from its complex with geminin. By establishing competitive regulation, geminin functions as a coordinator of developmental and proliferative control.

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Acknowledgements

We thank D. Duboule, A. Dutta, C. J. Tabin, S. Potter, R. Maas and H. Koseki for plasmids and antibodies, M. Pitulescu for discussions, J. Wittbrodt for communication and discussion of unpublished results, and P. Gruss and D. Gallwitz for their continuous support. This work was funded by the Max Planck Society and a DFG grant.

Author information

Correspondence to Michael Kessel.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

a, b, Subcellular co-localization of Geminin and Rae28/Mph1 or Mel18. (JPG 63 kb)

Supplementary Figure 2

Geminin inhibits transcriptional activation by Hoxa11 or Hoxb7. (JPG 35 kb)

Supplementary Figure Legends (DOC 28 kb)

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Further reading

Figure 1: Isolation of Hox and Scmh1 as geminin-binding proteins.
Figure 2: Geminin associates with the polycomb complex and Hox regulatory DNA elements in vivo.
Figure 3: Geminin modulates the anterior boundary of endogenous Hoxb9 transcription in the avian neural tube.
Figure 4: The geminin–Hox interaction inhibits DNA binding and competes with Cdt1–geminin complex formation.

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