Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes

Carlos Company, Matthias Jürgen Schmitt, Yuliia Dramaretska, Michela Serresi, Sonia Kertalli, Ben Jiang, Jiang-An Yin, Adriano Aguzzi, Iros Barozzi and Gaetano Gargiulo ()
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Carlos Company: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Matthias Jürgen Schmitt: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Yuliia Dramaretska: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Michela Serresi: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Sonia Kertalli: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Ben Jiang: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Jiang-An Yin: University Hospital Zurich
Adriano Aguzzi: University Hospital Zurich
Iros Barozzi: Medical University of Vienna
Gaetano Gargiulo: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Descriptive 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 synthetic cis-regulatory DNA (LSD), a computational framework leveraging phenotypic biomarkers and trans-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 custom cis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrate LSD with a computational ranking of phenotypic specificity of putative cis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters. Applied to broadly expressed genes from human and mouse tissues, LSD generates functional housekeeper-like sLCRs compatible with size constraints of AAV vectors for gene therapy applications. A mesenchymal glioblastoma reporter designed by LSD outperforms previously validated ones and canonical cell surface markers. In genome-scale CRISPRa screens, LSD facilitates the discovery of known and novel bona fide cell-state drivers. Thus, LSD captures core principles of cis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.

Date: 2024
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DOI: 10.1038/s41467-024-45069-6

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