Ann Harris laboratory

The main research focus in the laboratory is on transcriptional networks that coordinate gene expression in human epithelia. The unique properties of the epithelia lining the respiratory, digestive and reproductive systems are determined by transcription factors that establish and maintain the specific program of differentiation. Our interest in this topic developed through elucidation of the regulatory mechanisms for a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which when mutated causes the devastating inherited disease cystic fibrosis. CFTR encodes a chloride ion channel that is critical to the function of many epithelia. The CFTR gene encompasses nearly 200 kb of genomic DNA which is isolated within a single transcriptional domain. Within this, distal cis-acting regulatory elements are brought into close proximity with the gene promoter to modulate its activity. We identified many of the cell-type-selective transcription factors (TFs) that bind to these cis-elements. In recent work we revealed the targets for several of the key TFs genome wide, using ChIP-seq together with open chromatin mapping by DNase-seq. These studies enabled us to start determining the transcriptional networks that control epithelial cell identity and how individual TFs contribute to this coordinated gene expression. In a closely related project we are investigating the molecular basis of genetic elements affecting lung disease severity in CF. A genome-wide association study (GWAS) performed by others demonstrated that SNPs at Chr11:p13 tracked with this phenotype. These SNPs lie in an intergenic region that is flanked on one side by two epithelial-selective TFs and on the other by a gene involved in apoptosis. We are using a range of state of the art techniques to determine how this region of chromosome 11 impacts lung disease. Additional research interests in the laboratory include epithelial reprogramming in pancreas cancer.