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Cell. 2019 Jun 27;178(1):229-241.e16. doi: 10.1016/j.cell.2019.05.019. Epub 2019 Jun 20.

DNA Microscopy: Optics-free Spatio-genetic Imaging by a Stand-Alone Chemical Reaction.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: jwein@broadinstitute.org.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02140, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: aregev@broadinstitute.org.
3
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA; McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: zhang@broadinstitute.org.

Abstract

Analyzing the spatial organization of molecules in cells and tissues is a cornerstone of biological research and clinical practice. However, despite enormous progress in molecular profiling of cellular constituents, spatially mapping them remains a disjointed and specialized machinery-intensive process, relying on either light microscopy or direct physical registration. Here, we demonstrate DNA microscopy, a distinct imaging modality for scalable, optics-free mapping of relative biomolecule positions. In DNA microscopy of transcripts, transcript molecules are tagged in situ with randomized nucleotides, labeling each molecule uniquely. A second in situ reaction then amplifies the tagged molecules, concatenates the resulting copies, and adds new randomized nucleotides to uniquely label each concatenation event. An algorithm decodes molecular proximities from these concatenated sequences and infers physical images of the original transcripts at cellular resolution with precise sequence information. Because its imaging power derives entirely from diffusive molecular dynamics, DNA microscopy constitutes a chemically encoded microscopy system.

KEYWORDS:

inverse problems; machine learning; microscopy; spatial transcriptomics

PMID:
31230717
PMCID:
PMC6697087
[Available on 2020-06-27]
DOI:
10.1016/j.cell.2019.05.019

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