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Spatial Transcriptomic Approach Offers View of Gene Expression in Tissue

COLD SPRING HARBOR, NY (GenomeWeb) – By overlaying a thin slice of tissue atop a high-density array, researchers can begin to see just where in that tissue various genes are expressed, Fredrik Salmén from Sweden's Royal Institute of Technology said Tuesday during a presentation at the Biology of Genomes meeting.

Spatial transcriptomics is a "method we developed to combine morphological and gene expression data," Salmén said.

He and his colleagues have tested this approach out on mouse olfactory bulbs, and Salmén noted it could be applied to a range of other sample types, especially as improvements are made to resolution.

The tissue section is placed onto a glass slide that contains thousands of features, each with millions of nucleic acid probes. These probes also include a spatial barcode that tells the researchers just where on the slide any probe in particular is situated.

After the tissue is added to the array, it is stained and imaged to capture its morphological features. The mRNA in the tissue then seeps out to hybridize with the barcoded probes, and cDNA libraries containing the nucleic acid transcript sequence and the barcoded sequence are generated for paired-end sequencing.

From this, Salmén said, the method provides information on which genes are expressed in various regions of the tissue sample.

A key requirement for this approach to work and preserve spatial information, he added, is to be sure that when mRNA leaves the tissue, it transfers vertically down to the waiting probes below, rather than horizontally to nearby probes. Using fluorescently tagged probes, Salmén and his colleagues found little evidence of such sideways leakage, leading Salmén to say that he was confident that there was low diffusion.

Using the Allen Brain Atlas as a reference, he and his colleagues tested how well their spatial transcriptomics approach was able to determine where certain genes were expressed within mouse olfactory bulbs. This tissue is made up of various regions such as the mitral cell, glomeruli ring, and nerve layers.

For a number of genes — including housekeeping gene Actb and the axon growth and guidance gene Sema3a, among others — the data from the spatial transcriptomics approach corresponded with that of the Allen Brain Atlas.

Additionally, the expression of these genes could distinguish between the various regions of the mouse olfactory bulb tissue, as gauged by a principal components analysis. For example, Salmén said the core pear-shaped region could be distinguished from the rest of the tissue by the expression of five genes: Camk2a, Pcp4, Pnk, Camk4, and Nrgn.

He and his colleagues are now applying this approach to study other tissues, including breast, prostate, melanoma, and brain cancer tissue samples, as well as heart cell samples and plant samples.

At the same time, Salmén said they want to further improve the approach so that it can examine full-length mRNAs as well as microRNAs, and to increase the resolution to the single-cell level.

"This is something we've been aiming for the entire time," he said.