Researchers are developing new technologies to reveal new insights into brain function and disease

This new technology is helping researchers better understand the mechanisms involved in gene expression.

John Velasco

1:05 am April 19, 2023

Contributing reporter

Zoe Berg, Senior Photographer

Recently published The Yale-led study provided an unprecedented level of detail in understanding the molecular mechanisms governing gene expression directly in the spatial context of the tissue. The research could help leading scientists discover crucial advances in life science and biomedical research.

The study uses innovative spatial multi-omics technologies that can map epigenome and transcriptome on the same tissue area at nearly unicellular resolution. Spatial transcriptomics — method used to profile the expression of RNA transcripts in

cells in sections of intact tissue—allowed the spatial mapping of gene expression.

“Extending the limits of modalities and precision, this spatial omics technology offers unprecedented mapping of the transcriptome and epigenome in the same tissue slice,” wrote Yan Xiao, a postdoctoral fellow in Columbia’s Nanotherapy and Stem Cell Engineering Laboratory and co-author of this study. “In a spatially resolved manner, the study provided insight into how the epigenome regulates cell fates and cellular states in the mouse embryo, mouse brain, and human brain.”

Previously, researchers were able to map chromatin accessibility and histone modifications in different tissues. With these new spatial multi-omics technologies, researchers can conduct collaborative 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 such as cancer, diabetes, autoimmune conditions, and neurodegenerative disorders.

Spatial multi-omics techniques use 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 multiomics approaches with imaging techniques—such as multiplexed immunofluorescence or fluorescence in situ hybridization — researchers can precisely identify and distinguish individual cells within each pixel.

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

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

Boldrini explained that this technology could be useful in deciphering the biology of cancer tissue and other diseases. It can also, she noted, be “very successful” when applied to studying the brain because “the brain is layered, segmented and heterogeneous” and each area of ​​the brain contains different cells that perform different functions.

As a result, according to Boldrini, this technology uses a spatial approach that can provide “much 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 gain new insights into how cell identity determined at the level of chromatin regulation is translated into gene expression at the mRNA level,” writes Marek Bartošović, researcher at Stockholm University and co-author of this study.

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

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

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

“We would be excited to apply these advanced techniques to 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. “Helped by the tools developed in this study, the organoid approach may offer an intriguing platform for precision psychiatry.”

The research was published in the journal Nature.

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