PhD defence P. (Parisa) Dashti

Below is a brief summary of the dissertation:

This summary emphasizes key findings on the complex epigenetic regulation of osteogenesis. The differentiation process is coordinated by various enzymes, receptors, and transcription factors. This thesis shows that SMYD2, Class I PRMTs (PRMT1, PRMT4/CARM1), and EZH2 jointly control osteoblast differentiation through different pathways. These findings suggest that osteogenic strategies potentially could result in multiple drugs to promote bone formation. Further research is needed on the interaction of EZH2 with Wnt/β-catenin and interferon signaling, because these pathways may jointly determine mesenchymal differentiation. Future studies should clarify how EZH2-dependent epigenetic pathways work with receptor-mediated cell signaling pathways that activate or suppress transcription factors.

These studies are based on the concept that identification of druggable epigenetic regulators can support new strategies for bone formation. Inhibitors for SMYD and PRMT may stimulate osteogenic differentiation, confirming previous findings for EZH2 inhibitors. Pilot experiments showed that both SMYD and PRMT inhibitors can stimulate osteogenesis with EZH2 inhibitors. Additional research is necessary to understand how these agents interact at the epigenetic level to use drug combinations. It is unclear if these drugs target the same or different molecular pathways. Given the many known epigenetic proteins and the success with a few screened classes, additional epigenetic enzymes that can be pharmacologically inhibited could be examined. Moreover, translational studies are needed to investigate potential inhibitors as therapies for various bone-related disorders in dental and skeletal applications, including regenerative bone medicine and surgical bone repair.