Identifying cis-regulatory regions for targeted therapeutic expression
Year: 2019
Type: other
Abstract: Expression of the delivered gene in cells other than those clinically relevant (i.e. off-target) is undesirable and a major concern in gene therapy applications. Knowledge of cis-regulatory regions (CRRs) can be used to design cis-regulatory sequences (CRSs) that restrict the expression of the delivered gene to the target cells. OnTarget automates the design of selective CRSs. It incorporates three components: 1) an underlying data repository, GUD (Genomic Universal Database), linking thousands of public regulatory genomics datasets from hundreds of human samples; 2) a module to identify CRRs potentially controlling the expression of genes in sample-specific contexts; and 3) a module to link CRRs to genes (under development). Identification of CRRs is done as follows: 1) select samples relevant to the target cells; 2) identify one gene differentially expressed in these samples; and 3) predict the CRRs of that gene based on a combination of regulatory genomic features and conservation. Next, identified CRRs are linked to the gene based on correlation of transcription factor binding. The CRS is achieved by assembling an optimal subset of the CRRs. As an example, we show the application of OnTarget to design CRSs targeting specific cells within the brain and eye.
Institution: University of British Columbia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4416516524