Zoe Berg, Senior Photographer

A recently published Yale-led study provided an unprecedented level of detail in understanding the molecular mechanisms governing gene expression directly within the spatial context of tissue. The research could help lead scientists in discovering crucial advancements in life science and biomedical research.

The study used groundbreaking spatial multi-omics technologies that are capable of mapping the epigenome and transcriptome on the same tissue section at near-single-cell resolution. Spatial transcriptomics — a method used to profile the expression of RNA transcripts in

cells within sections of intact tissue — has enabled the spatial mapping of gene expression. 

“Pushing the limits of modalities and precision, this spatial omics technology offers an unprecedented mapping of transcriptome and epigenome in the same slice of tissue,” wrote Yang Xiao, a postdoctorate student at the nanotherapeutics and stem cell engineering lab at Columbia and co-author of this study. “In a spatially resolved manner, the study provided insights into how epigenome regulates cell fates and cell states in the mouse embryo, the mouse brain and the human brain.”

Previously, researchers were able to map chromatin accessibility and histone modifications in various tissues. With these new spatial multi-omics technologies, researchers can conduct joint profiling of the epigenome and transcriptome in the same tissue section, providing a more comprehensive understanding of cellular states and organization.

These technologies have a wide range of applications in biological and biomedical research fields, including diseases like cancer, diabetes, autoimmune conditions and neurodegenerative disorders. 

The spatial multi-omics techniques utilize short DNA sequences as barcodes for each grid pixel of a tissue section, providing detailed spatial maps of epigenetic and transcriptional states. By combining these spatial multi-omics approaches with imaging techniques — such as multiplexed immunofluorescence or fluorescence in situ hybridization — researchers can accurately identify and distinguish individual cells in each pixel. 

This new method allows for the simultaneous mapping of gene expression and chromatin state, providing valuable information about genetic determinants of cell identity.

“This new microfluidic technology has been created by bioengineers to perform high resolution multiome analysis in large intact tissue areas.” wrote Maura Boldrini, director of the Quantitative Human Brain Biology Institute and co-author of this study.

Boldrini explained that this technology can be helpful in deciphering the biology of cancer tissue and other diseases. Furthermore, she noted, it can be “very successful” when applied to studying the brain as “the brain is layered, segmented and heterogeneous,” and each area of the brain contains different cells that perform distinct functions.

As a result, according to Boldrini, this technology uses a spatial approach that can provide “a lot more information than a single cell approach in homogenized tissue.”

“The main motivation for this project was to push the boundaries of spatial multimodal technologies and to gain new insights into how the cell identity specifies at the level of chromatin regulation translate into gene expression at the mRNA level,” wrote Marek Bartosovic, a researcher at Stockholm University and co-author of this study.

The results of the study showed that the newly-developed method allowed researchers, for the first time, to measure position within the tissue, gene expression and chromatin state with high resolution.

According to Bartosovic, future research plans include expanding the set of co-profiled modalities to capture the cellular state at the level of DNA, chromatin, mRNA expression and protein expression. 

Moreover, Boldrini and Xiao noted that the researchers are interested in applying this technology to study areas in the brain that contain circuits involved in psychiatric diseases such as depression and suicide, Alzheimer’s disease, other types of dementia and COVID-19 brain pathology.

“We would love to apply these advanced techniques to patient-iPSC-derived brain organoids for neuropsychiatric disease modeling and drug discovery,” wrote Kam Leong, Samuel Y. Sheng professor of biomedical engineering at Columbia and co-author of this study. “Aided by the tools developed in this study, the organoid approach can offer an intriguing platform for precision psychiatry.”

The study was published in the journal “Nature.”