Is Next-level Spatial Analysis of DNA Process Possible?

The Findings

Researchers in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia and the University of Pennsylvania developed a new method to understand the full tissue context of DNA methylation — small chemical modifications to DNA that help program cell gene activity — in greater detail than ever before.

The team introduced a technology for spatial co-profiling of DNA methylome and transcriptome (Spatial-DMT) at near single-cell resolution in murine tissue samples, providing a detailed map of known methylation biology and its interplay with gene expression.

Why It Matters

Seeing DNA changes up close and in specific areas within tissue is essential for understanding how our bodies work. Yet the capacity to spatially profile DNA methylation — which controls which genes are turned on or off — is lacking.

DNA methylation is an epigenetic mechanism known to affect gene expression. The human body has the capacity to mark certain genes by adding tiny chemical tags onto the DNA. When a gene is methylated, it is usually less active or completely turned off. When it’s not methylated, the gene is more likely to be turned on and used. This helps cells remember what they’re supposed to do — think sticky notes — but it can change over time based on factors such as aging, diet, or the environment. Problems with DNA methylation can be linked to diseases such as cancer.

This new method expands the capabilities of spatial multi-omics and may offer a valuable tool for better understanding key biological questions, from the mechanisms of Alzheimer’s disease to how cancer responds to treatment.

Who Conducted the Study

Co-corresponding and co-senior authors Wanding Zhou, PhD, a Computational Scientist in CHOP’s Center for Computational and Genomic Medicine; and Yanxiang Deng, PhD, an Assistant Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania, led the collaborative effort.

How They Did It

To achieve spatial co-mapping of DNA methylation and RNA, Spatial-DMT uses microfluidic devices to flow barcode reagents in two perpendicular directions, making a grid of unique barcodes per pixel as determined in a 2D spatial coordinate system. This approach profiles the DNA and RNA from the same spatial location, since the barcode records the unique spatial information. Integrating both data types gives a better picture of “where things are different,” as opposed to using just RNA or just DNA methylation alone, according to Dr. Zhou.

Quick Thoughts

“Our findings reveal new approaches for uncovering how environment and biology shape health across tissues and populations,” Dr. Zhou said. “With our new method, we can reconstruct the dynamics of DNA methylation with a much better resolution for how these environmental changes interact with the cellular change.”

What’s Next

“In the future, Spatial-DMT could be expanded to include proteins or metabolites, giving an even fuller view of how cells work within tissues,” Dr. Deng said. “We also aim to adapt the method for standard hospital samples preserved in formalin-fixed paraffin-embedded (FFPE) blocks, which would make it more practical for clinical use.”

Where the Study Was Published

The findings were published in Nature.