Spatial transcriptomic imaging of an intact organism using volumetric DNA microscopy

Area of Science:

• Molecular Biology
• Genomics
• Bioimaging

Background:

• Complex tissues like lymphatic, nervous, and tumor systems involve intricate 3D interactions within unique microenvironments.
• Existing spatial transcriptomic and genomic methods often require prior knowledge of spatial organization or genetic sequences.

Purpose of the Study:

• To develop a novel technology for simultaneous volumetric imaging of transcriptomes, genotypes, and morphologies in biological tissues.
• To enable spatial genetic measurements in three dimensions without reliance on prior templates or knowledge of genetic sequences.

Main Methods:

• Extension of DNA microscopy into three dimensions to image 10^7 molecules by forming a distributed intermolecular network of proximal unique DNA barcodes.
• Sequencing of the DNA-encoded network and inference of molecular positions using geodesic spectral embeddings, a dimensionality reduction technique.
• Application of whole-transcriptome volumetric DNA microscopy to intact zebrafish embryos.

Main Results:

• Demonstrated successful three-dimensional image inference that recapitulates zebrafish morphology and known gene expression patterns.
• Validated the ability to capture the spatial organization of gene sequences within the tissue.
• The method provides joint resolution of genomics and morphology in biological tissues.

Conclusions:

• The developed technology enables unprecedented volumetric imaging of transcriptomes, genotypes, and morphologies in a single measurement.
• This approach overcomes limitations of template-dependent spatial genetic measurements, opening new avenues for biological tissue analysis.
• The findings pave the way for detailed joint resolution of genomics and morphology in complex biological systems.