Ann Harris, PhD
Professor of Pediatrics
Director, Human Molecular Genetics Program
Children's Memorial Research Center
Research Interests:
Regulation of gene expression.
The cystic fibrosis transmembrane conductance regulator gene (CFTR), which when mutated causes cystic fibrosis, shows a tightly regulated pattern of spatial and temporal expression. The molecular basis for this regulation has not been fully elucidated but it is clear that key regulatory elements lie outside the gene promoter. We have identified regulatory elements flanking the gene and within introns and mapped the likely functional cores of these elements by comparative genomics. We are investigating i) how these regulatory elements function with the CFTR promoter, and ii) how modifications in chromatin structure modulate expression of the gene in vivo. We are also studying the developmental regulation of CFTR expression. These studies are of direct relevance to CF gene therapy.
Mucin glycoprotein structure and function.
Mucins are heavily O-glycosylated glycoproteins that play a key role in the human airways and are also important in the function of many other epithelia including those lining the pancreas and intestine. Mucins may be secreted from cells via granules or exist as membrane-tethered molecules that can be released from the cell surface. The modifications of mucins that result in the phenotype of CF and other epithelial diseases and are associated with many cancers are poorly understood. We are investigating the molecular biochemistry of membrane-tethered mucins which are co-translationally cleaved, processed and transported to the cell-surface as dimers or multimers. Mucin release from the cell surface, subsequent to ligand binding or other extracellular stimuli, triggers intracellular signalling cascades. Modulation of the release of membrane-tethered mucins may be of therapeutic benefit.
Selected Publications:
Blackledge, N. P., Ott, C. J., Gillen, A. E. and Harris, A. (2009). An insulator element 3' to the CFTR gene binds CTCF and reveals an active chromatin hub in primary cells. Nucleic Acids Res.
Evans, J. R., Kelly, D. L., Morris, K. J., Arvide, E. M. and Harris, A. (2008). RNA interference-mediated inhibition of hepatocyte nuclear factor 1alpha identifies target genes. Biochim Biophys Acta 1779, 341-6.
Ott, CJ, Suszko M, Blackledge, NP, Crawford, GE, Harris A. (2008). A complex intronic enhancer regulates expression of the CFTR gene by direct interaction with the promoter. Journal of Cellular and Molecular Medicine. In Press.
Blackledge, N. P., Carter, E. J., Evans, J. R., Lawson, V., Rowntree, R. K. and Harris, A. (2007). CTCF mediates insulator function at the CFTR locus. Biochem J 408, 267-75.
Harris, A., Harris, H. and Hollingsworth, M. A. (2007). Complete suppression of tumor formation by high levels of basement membrane collagen. Mol Cancer Res 5, 1241-5.
