Clonal analysis reveals epigenetic drivers of craniofacial birth defects

During embryogenesis, mesenchymal stem cells regulate cell division rates and cell differentiation in order to properly form skeletal elements like cartilage and bone, but how this is accomplished remains mysterious.

Common birth defects like facial clefts, craniosynostoses, and skeletal dysplasias (together affecting ~1/600 newborns) are caused by improper development of bones and cartilage in the embryo.

These diseases are incurable in part because of a limited understanding of molecular mechanisms disrupted in disease states.

As a result, etiological explanations are missing for disease-related single nucleotide polymorphisms (SNPs), especially those in noncoding regions.

Using a novel mouse model to perform high-throughput clonal lineage tracing combined with multiplexed gene perturbations, I will investigate the genetic and epigenetic bases of cell fate decisions underlying mesenchymal tissue shaping in normal and altered craniofacial development.

I will test the hypothesis that orphan SNPs affect gene regulatory cascades that balance cell proliferation with cell differentiation tempo.

Specifically I will investigate four single-gene diseases (mutations in FGFR2, PTCH1, SOX9, PAX1) to identify face-related SNPs within regulatory elements both upstream and downstream of each gene in facial mesenchyme.

The project will reveal a regulatory feedback network involving chromatin architecture and cell signaling to balance proliferation with fate decisions of stem cells in vivo.