Symbolic recording of signalling and cis-regulatory element activity to DNA

Wei Chen (), Junhong Choi, Xiaoyi Li, Jenny F. Nathans, Beth Martin, Wei Yang, Nobuhiko Hamazaki, Chengxiang Qiu, Jean-Benoît Lalanne, Samuel Regalado, Haedong Kim, Vikram Agarwal, Eva Nichols, Anh Leith, Choli Lee and Jay Shendure ()
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Wei Chen: University of Washington
Junhong Choi: University of Washington
Xiaoyi Li: University of Washington
Jenny F. Nathans: University of Washington
Beth Martin: University of Washington
Wei Yang: University of Washington
Nobuhiko Hamazaki: University of Washington
Chengxiang Qiu: University of Washington
Jean-Benoît Lalanne: University of Washington
Samuel Regalado: University of Washington
Haedong Kim: University of Washington
Vikram Agarwal: University of Washington
Eva Nichols: University of Washington
Anh Leith: University of Washington
Choli Lee: University of Washington
Jay Shendure: University of Washington

Nature, 2024, vol. 632, issue 8027, 1073-1081

Abstract: Abstract Measurements of gene expression or signal transduction activity are conventionally performed using methods that require either the destruction or live imaging of a biological sample within the timeframe of interest. Here we demonstrate an alternative paradigm in which such biological activities are stably recorded to the genome. Enhancer-driven genomic recording of transcriptional activity in multiplex (ENGRAM) is based on the signal-dependent production of prime editing guide RNAs that mediate the insertion of signal-specific barcodes (symbols) into a genomically encoded recording unit. We show how this strategy can be used for multiplex recording of the cell-type-specific activities of dozens to hundreds of cis-regulatory elements with high fidelity, sensitivity and reproducibility. Leveraging signal transduction pathway-responsive cis-regulatory elements, we also demonstrate time- and concentration-dependent genomic recording of WNT, NF-κB and Tet-On activities. By coupling ENGRAM to sequential genome editing via DNA Typewriter1, we stably record information about the temporal dynamics of two orthogonal signalling pathways to genomic DNA. Finally we apply ENGRAM to integratively record the transient activity of nearly 100 transcription factor consensus motifs across daily windows spanning the differentiation of mouse embryonic stem cells into gastruloids, an in vitro model of early mammalian development. Although these are proof-of-concept experiments and much work remains to fully realize the possibilities, the symbolic recording of biological signals or states within cells, to the genome and over time, has broad potential to complement contemporary paradigms for how we make measurements in biological systems.

Date: 2024
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DOI: 10.1038/s41586-024-07706-4

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