TRANCERs: Engineering enhancers into autonomous tissue-specific expression cassettes

Abstract

Due to the scarcity of autonomous cell-specific promoters, control of transgene expression remains a major challenge, particularly for therapeutic applications where specificity and compactness are critical. We developed TRANCERs (TRanscriptionally Autonomous enhaNCERs), a modular system that converts gene regulatory elements (enhancers) into cell-specific standalone promoters by coupling enhancer activity with known and novel principles of transcript stability and nuclear export. This vastly increases the current repertoire of highly specific promoters available to science. We show TRANCERs drive lineage-restricted expression of genes both in vitro and in vivo, and that this expression pattern faithfully mirrors the activity of the enhancer element used. Their compact footprint and resistance to epigenetic silencing makes them ideally suited for payload-limited delivery systems such as viral vectors. TRANCERs provide a broadly applicable strategy for precise and programmable control of gene expression, enabling highly specific and customisable expression patterns for both basic research and gene-based therapies.