Functional genomics to identify miRNA targets in the developing face

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DESCRIPTION (provided by applicant): Craniofacial developmental defects are common, affecting about 1 in 100 human infants, with high financial and human costs. By better understanding the mechanisms of facial development, we hope to develop better prevention, diagnostic and treatment strategies. FaceBase currently houses high-throughput data on promoters, transcripts and microRNAs (miRs) that are used in mouse facial development. To effectively use these data to understand the genetic programs, the cellular interactions, and hence the mechanisms underlying morphogenesis of the face, they must be integrated amongst themselves and with more general knowledge. microRNAs (miRNAs) are an important component of genetic programs and have critical roles in facial development. They generally act through down-regulating target messenger RNAs (mRNAs). The average miRNA targets over 200 mRNAs, and many mRNAs are regulated by multiple miRNAs. The targets of a given miRNA are generally functionally related, so miRNAs regulate biological functions as well as of individual genes. The challenge for genomic-level miRNA studies is to identify the individual genes and biological functions that are targeted by each miRNA. This proposal utilizes existing mRNA and miRNA expression data from the developing mouse face and integrates it with functional genomics knowledge to provide a systems-level view of the role(s) of miRNAs in facial development. The computational approach is based on the hypothesis that miRNAs orchestrate genetic programs for cell fate and/or differentiation through coordinated regulation of suites of functionally related genes. It identifies and assigns probabilities to genes, pathways and biological processes that are likely to be regulated by miRNAs. It then tests these predictions in a cranial neural crest cell line. By comparing computed probabilities to validation rates, this will provide a statistical test for the general hypothesis that miRNAs orchestrate genetic programs. These data will provide an overview of the role(s) of miRNAs in facial development as well as which miRNAs are likely to have the most profound effects. They will also identify the genes, pathways and biological processes that mediate those effects. Given the relative ease with which microRNAs can be manipulated in vitro and in vivo, this information has the potential to lead to more effective tissue engineering treatments for human facial birth defects.