Histone post-translational modifications regulate chromatin structure and accessibility to facilitate transcriptional activation or repression of neighboring genes. Countless aspects of organismal development and differentiation rely upon change in chromatin environment to regulate gene activity. The enzymes that catalyze addition or removal of histone modifications offer plasticity to alter chromatin states and gene expression during changes in cellular identity. Appropriate craniofacial development is largely dependent on cranial neural crest stem cell biology. This multi-potent stem cell population is specified in early mammalian embryology for migration to anterior facial positions and directed differentiation towards all facial bone and cartilage. Chromatin-modifying factors play important roles in neural crest transcriptional transitions as mutations in several histone modifying or remodeling enzymes underlie pathogenesis of human craniofacial disorders. One of these disorders, Kabuki syndrome, is caused by mutations in either a histone H3 lysine 27 demethylase (UTX) or a histone H3 lysine 4 methylase (KMT2D). UTX and KMT2D associate biochemically, thus coordinated removal of repressive H3K27 methylation and addition of active H3K4 methylation may regulate neural crest transcriptional activation and facial structure. The experiments outlined in this proposal utilize mouse genetics to model KMT2D neural crest function in the Kabuki craniofacial disorder. Histological, cellular, and genomic approaches will elucidate the cellular and molecular mechanisms of chromatin factors in disease pathogenesis.
Many human craniofacial syndromic disorders result from haploinsufficiency of chromatin modifying proteins. These enzymes regulate histone post-translational modifications or nucleosomal structure to alter the transcriptional state of large genic groups. Studying how chromatin modifiers function at the cellular, molecular, and genomic levels is crucial towards elucidating craniofacial disorder pathogenicity. Due to reversibility of histone post-translational modifications, chemical inhibitors of these enzymes have been generated for therapeutic approaches that may be applicable towards syndromic features.
