Our lab is interested in epigenetic gene regulation dictated by chromatin modifications. We examine the mechanism of stable inherited transcriptional repression by Polycomb-group (Pc-G)/MLL protein complexes, and the effects of deregulation of these genes on development, cell cycle control, and cancer formation. Studies on Pc-G/MLL have demonstrated that beside their function in controlling the expression of Hox genes, Pc-G/MLL play a central role in cell proliferation through the control of the INK4ab/ARF locus.
We focus on the regulation of the INK4b-ARF-INK4a tumour suppressor locus and its role in the achievement of cellular senescence, a permanent growth arrest directed by a wide range of stress. Senescence is view as a defence against oncogenic insults, and defines limits on the proliferative potential of stem and progenitor cell populations. In the course of tumourigenesis, an enrichment of senescent cells is often seen in pre-neoplastic lesions, (lung adenomas and other cancer). This observation together with the fact that mutations disabling senescence are required to cooperate in cancer progression and suggest that senescence constitutes a bona fide tumour suppressor mechanism.
Our current goal is to determine how different signalling pathways affect transcription of the locus by altering Polycomb/MLL binding at the Ink4/Arf locus and as a conscequence the state of histone modifications in the neighbouring chromatin.
We use knock out Polycomb/MLL mouse models to dissect the function between tumor suppression and aging