Genomic and Functional Analyses of Conserved Noncoding Regions in Vertebrates

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The major aims of the Genomic Functional Analysis Section are to identify cis-and trans-acting functional elements in vertebrate genomes. Approaches to find these elements incorporate computational and experimental components including whole-genome comparative analyses, predictions based on machine learning techniques and experimental testing. Major focus areas include identifying bidirectional promoters in the human genome and elucidating their involvement in cancer, understanding the relationship between sequence-based regulatory features and expression patterns from alternative promoters, and developing high throughput assays to identify silencer elements in the human genome. All research avenues converge on the identification of transcription factor binding sites, which are the basic components of gene regulation. Approaches to identify proteins that bind to these regulatory sites are underway for all three of the above research areas. During the course of our work, novel motifs were implicated as silencers and new biological insights were revealed for the genomic structure of alternative promoters. A collaborative effort has been established to define regulatory networks that control gene expression in pathways involved in cancer. These studies will address the methodology of network modeling and identify new targets for cancer diagnostics and testing. These targets are being identified through computational approaches. Experimental follow-up is being done using bisulfite sequencing to assess aberrant methylation of promoter regions, in collaboration with the NIH Sequencing Facility. The analysis aims to study the methylation patterns of promoters in ovarian cancer compared to normal tissue.