Dr. Elnitski is a molecular and computational biologist who studies noncoding functional elements in vertebrate genomes. The functional sequences that encode proteins — genes — make up less than 2 percent of the human genome. Functional elements found in the remaining 98 percent of the genome, such as promoters, enhancers, silencers, and RNA-splicing signals, have important biological roles, particularly in regulating the temporal and spatial patterns of gene expression. The study of these noncoding functional elements is crucial for establishing a complete understanding of normal cell function.
Dr. Elnitski's group uses both bioinformatic and experimental approaches to identify noncoding functional elements in vertebrate genomes. For instance, they use cross-species comparisons to zero-in on sequences that have remained relatively unchanged throughout evolution; genomic regions with high degrees of conservation often contain functionally important sequences. These data are useful for training machine-learning algorithms that predict the potential of genomic sequences to be regulatory (i.e., those that control gene expression) or neutrally evolving (i.e., those that are not under selection to remain the same). Such predictions are used to narrow the amount of genomic material that must be examined to find important regulatory sequences.
In addition, Dr. Elnitski's laboratory is investigating less characterized functional elements in the human genome. In one project, her group is exploring mutations in exonic splicing enhancers (ESEs) that correlate with aberrant splicing patterns in coding regions of genes. Present in most mammalian exons, ESEs are short sequences that direct the process of RNA splicing, in which introns are removed from the primary transcript and the exons are then joined together, producing a mature messenger RNA (mRNA). ESEs also play a role during precursor mRNA editing in the selection of correct splice sites, which are located at the boundaries between exons and introns. The correct choice of splice sites is essential not only for the proper production of proteins, but also for the generation of alternatively spliced mRNA forms (such as those seen with exon skipping) that often occur in specialized tissues or at different developmental stages. As part of this project, Dr. Elnitski seeks to investigate the role of ESEs in unnatural exon skipping and their relevance to several cancers and inherited diseases in humans. For example, exon skipping is caused by genetic mutations in the BRCA1 and CFTR genes, which are associated with breast cancer and cystic fibrosis, respectively. For this study, her group is building probabilistic models to identify mutations that disrupt RNA splicing.
Dr. Elnitski's group is also examining the regulation of transcript initiation in the human genome. One project focuses on the role of bidirectional promoters, which are defined as the regulatory regions between two adjacent genes whose transcription initiation sites are neighboring but oriented away from each other. This promoter architecture is often found in DNA repair genes and genes that are implicated in somatic cancers. Thus, the identification of all genes associated with this promoter structure might provide new insights into human disease. Some sets of genes regulated by bidirectional promoters have been found to be coexpressed, suggesting that common transcription factor-binding sites are involved in their regulation. Furthermore, aberrant methylation of these promoters can lead to silencing of their expression; in the case of bidirectional promoters, expression of both flanking genes is affected. Dr. Elnitski has mapped all bidirectional promoters in the human genome using computational techniques, and these results are being used to find targets of aberrant methylation in ovarian cancer tumor samples.
Finally, Dr. Elnitski is extensively involved in NHGRI's ENCODE (Encyclopedia of DNA Elements) project, which aims to produce a comprehensive catalog of functional elements in the human genome. Specifically, she is mapping silencer elements using a novel experimental system. She is also identifying networks of bidirectional promoters across species to develop the first regulatory maps of orthologous promoter elements in sequenced mammalian genomes.
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Last Updated: July 13, 2011