A Platform Technology for High-Throughput Screening of Gene Regulatory Elements

Project Summary Abstract The goal of this proposal is to develop a novel high throughput platform for understanding gene regulatory elements in order to identify new drug targets for common diseases The human genome encodes approximately genes Understanding how those genes are regulated and how this correlates to complex cell phenotypes has long been a major focus of our team Follow up projects to the Human Genome Project such as the NIH funded Encyclopedia of DNA Elements ENCODE and the Roadmap Epigenomics Project have identified millions of putative regulatory elements across the human genome for many human cell types and tissues Importantly genome wide association GWA studies have strongly indicated that non coding regulatory elements determine the gene expression patterns responsible for most complex diseases including cancer cardiovascular disease diabetes and neurological disorders However the function of these regulatory elements and their relationships to these disease phenotype are largely unknown Additionally conventional screening technologies for perturbing cellular processes such as small molecules and RNA interference cannot directly target genomic regulatory elements To address this critical limitation and illuminate the fundamental genomic basis of these cell phenotypes we have recently developed epigenome editing technologies for directly and precisely activating and repressing genomic regulatory elements in their natural chromosomal location More recently we have developed a novel and robust method for using these tools for high throughput identification and quantification of gene regulatory element activity Here we propose to apply these methods to the discovery and validation of regulatory elements associated with cancer and cardiovascular disease as demonstration of this novel platform technology for understanding the genetic basis of complex disease This technology will be critical to translating modern advances in genetics and genomics into new drug targets diagnostics and personalized medicine catered to each patient genome Project Narrative The purpose of this STTR Phase I application is to develop novel methods to identify and characterize gene regulatory elements and non coding DNA mutations associated with complex disease with the goal of discovering new classes of drug targets and developing functionally informed diagnostics The academic partner Duke University has accumulated years of experience with characterizing regulatory elements and DNA variants using genome and epigenome editing strategies The small business partner Element Genomics Inc will be involved in developing novel high throughput methods and bioinformatics pipelines to robustly characterize andapos s of regulatory elements from any region of the genome and will show how perturbing these regulatory elements contributes to altered phenotype We propose to develop these methods by focusing on two model genes that have been shown to be involved in human disease The results from these Phase I studies will be used for future Phase II studies to identify novel small molecule drugs that impact the expression of those genes