Abstract
AbstractDescriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of syntheticcis-regulatory DNA(LSD), a computational framework leveraging phenotypic biomarkers andtrans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or customcis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrated LSD with a computational classifier to rank phenotypic specificity of putativecis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters.In silico, an LSD-unsupervised mesenchymal glioblastoma reporter outperformed previously validated ones. In genome-scale CRISPRa screens, it discovered known and novelbona fidecell-state-drivers. Thus, LSD captures core principles ofcis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献