MicroRNAs as epigenetic regulators of orofacial development

Environmental and genetic factors contribute significantly to the etiology of orofacial clefting, which is one of the most common of human congenital craniofacial malformations. Current biological thought now recognizes that epigenetics represents a fundamental contributing process in embryogenesis. Indeed, many of the mechanisms whereby environmental insults affect key pathways crucial for proper embryonic growth and development are increasingly thought to be mediated via the epigenome. Epigenetic regulators, such as microRNAs (miRNAs), play vital roles in the ontogeny of the orofacial region. Evidence for this comes from conditional knockouts of Dicer or DGCR8, genes encoding key enzymes in the miRNA biosynthetic machinery, in neural crest cells. Such knockouts result in a range of craniofacial/orofacial anomalies, including cleft palate and cleft lip. Epigenetic pathways may thus represent key vehicles in the regulation, and misregulation, of gene expression during normal and abnormal orofacial embryogenesis. Significant strides have been made in the last decade in identifying miRNAs and their target genes involved in lip and palate morphogenesis. Such morphogenetic processes include apoptosis, cell proliferation, cell differentiation, and epithelial-mesenchymal transition (EMT). While some of the miRNA-target gene interactions have been functionally validated, many exhibit causal relationships that await functional confirmation. A plethora of genes associated with cleft palate/cleft lip have now been identified that provides a veritable treasure trove of information that could be harnessed to identify novel miRNA candidates for further analysis. In this review, we summarize studies identifying miRNAs involved in various aspects of lip and palate morphogenesis and whose aberrant expression may result in orofacial clefts.