Complex gene regulatory networks and signaling cascades must be carefully regulated both spatially and temporally in order to orchestrate the formation of different tissues and organ systems. Epigenetic regulators and chromatin remodelers add a hierarchal level of control to the timely activation or repression of key developmental processes.

The formation of the craniofacial skeleton requires precise organization of tightly regulated cellular and molecular processes across multiple cell types and tissues. Important to proper craniofacial development is the development of cranial neural crest cells. This dynamic multipotent population of cells must undergo an epithelial-to-mesenchymal transition, migrate toward the pharyngeal arches and then begin differentiation toward chondrocytes and osteoblasts to form the cartilage and bone of the developing face. Alterations to the gene regulatory networks or signaling modules that govern cranial neural crest cell differentiation toward chondrocytes and osteoblasts can impact the development of these structures and lead to craniofacial defects including mandibular hypoplasia, cleft lip/palate, and middle ear defects, among others.

While the processes of cranial neural crest-derived chondrocyte and osteoblast differentiation and maturation have been well characterized, the upstream temporal and spatial regulation of the gene regulatory networks and signaling pathways facilitating these processes remain largely unresolved.

I have started investigating the conserved and diverging functional roles for two chromatin remodelers/transcription factors from the PRDM histone methyltransferase family, PRDM3 and PRDM16 in zebrafish and mouse craniofacial development (Shull et al, Dev Biol 2020). Recently, I have identified mechanistic roles for these two PRDMs in facilitating proper chondrocyte differentiation and maturation during craniofacial development. I have found that these paralogs function antagonistically of each other to balance Wnt/beta-catenin signaling both at the transcriptional and chromatin level. Loss of either leads to dysregulated Wnt/beta-catenin signaling which alters neural crest chondrocyte differentiation and maturation leading to compromised formation of craniofacial cartilage structures (Shull et al, Development 2022).

My research program will build upon these findings to explore new mechanisms of transcriptional and epigenetic regulation during the critical stages of cartilage and bone formation during craniofacial development.