The function of E2F6 in the Polycomb complex

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2005.Cataloged from PDF version of thesis.Includes bibliographical references.The E2F family of transcription factors are known cell cycle regulators that function at the G1/S transition. Unlike other E2Fs, E2F6 does not activate transcription and is not regulated by pocket protein binding. Instead, this protein appears to repress transcription through the recruitment of the Polycomb Group (PcG) complex. This complex is responsible for the maintenance of Hox gene expression patterns during development and thus ensures the correct anterior-posterior segmentation of the embryo. Genetic ablation of PcG proteins leads to posterior transformations of the axial skeleton as well as other developmental abnormalities such as hematopoietic, cerebellar and smooth muscle defects. The PcG complex has been implicated in cell cycle control since several of its members, including the oncoprotein Bmi 1, appear to repress the transcription of p1 6INK4A and pI 9 ARF. In order to determine the biological function of E2F6, we have generated and characterized E2f6'- mice and mouse embryonic fibroblasts (MEFs). The mutant mice are viable and survive into adulthood with similar lifespan as their littermate controls. Furthermore, the E2f6 null MEFs are indistinguishable from wild-type MEFs in asynchronous proliferation, cell cycle re-entry from quiescence, senescence and E2F target genes expression levels. These findings suggest that E2F6 does not play a major role in cell cycle control or that its function can be compensated by the action of other factors. In fact, preliminary results from combined loss of E2f6 and Bmil suggest that E2F6 may take part in the Bmi 1-mediated control of the cell cycle. Furthermore, we found that the loss of E2F6 results in posterior axial skeleton transformations that are reminiscent of the Bmil-deficient mice defects. The study of the E2f6;Bmil compound mutant mice revealed a dosage-dependent synergism between E2F6 and Bmi 1. These results indicate that E2F6 participates in segmentation during murine development. As a whole, our work has provided proof that E2F6 is a bonafide Polycomb Group protein and, at the same time, has opened the field to a number of interesting questions.by María F. Courel.Ph. D