Novel spatial multiomics techniques decipher the spatiotemporal lineage of mouse brain development

On May 25, Nature Methodology published the latest research results of Peng Guangdun, a researcher at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, who revealed a spatial multiomics technique called MISAR-seq. Jiang Fuqing, Qian Yingying, Zhu Miao and Zhou Xin are the co-first authors of the paper, and Peng Guangdun is the corresponding author. The research work was also assisted by Cui Guizhong, a researcher in the Guangzhou laboratory, and Chen Kai, a researcher at Kunming University of Science and Technology.

Peng Guangdun said that this technology through the microfluidic chip-dependent targeted barcode delivery system, while retaining the spatial position information of the cell, the capture of intracellular ATAC and RNA omics information was realized, and it was successfully applied to the study of the brain development mechanism of embryonic mice, which not only constructed a spatiotemporal multiomics map of mouse brain development for the first time, but also revealed the specific regulatory mechanism of cis-regulatory elements formed by promoters and enhancers in brain development.

Data quality for MISAR-seq. Photo courtesy of the research team

MISAR-seq has the ability to analyze RNA and ATAC information simultaneously on a sample at a spatial location. The researchers verified the data quality of MISAR-seq and found that the quality of the spatial biomics-based ATAC and RNA data was close to or better than that of its corresponding singleomics data, with the number of genes detected per unit data point roughly between 2500 and 3500. Further meta-analysis with single-cell data showed that the brain cell types captured by this technique also matched the brain structure annotations of the corresponding single cells.

The researchers integrated and analyzed the brain development data of mice with different developmental periods and containing two omics information, and developed bioinformatics tools based on the combination of spatial location limitation and image feature extraction, which effectively improved the “horizontal” and “vertical” integration ability of data between multiple different omics points in different periods, so as to draw a spatiotemporal multiomics map of mouse brain development. The results showed that whether MISAR-seq ATAC or RNA data alone or spatial clustering using both omics data at the same time, brain region division could be better performed, and the clustering results were consistent with the annotations of Allen Brain Atlas.

Based on the obtained MISAR-seq data, the researchers attempted to further explain the cascade regulatory relationship between chromatin opening and gene expression during corticogenesis by mapping the spatial and temporal trajectories of cortical development of the two omics. The study found that the direct cascade regulation of Pax6-Eomes-Tbr1 formation established the order and regional specificity of gene expression during mouse corticogenesis. These results show that multi-omics spatiotemporal trajectory analysis can better predict the important driving factors that determine cell fate, and can provide specific interaction patterns of TF, so as to exert precise regulation on the formation of complex structures such as cortex.

“In the future, we expect that MISAR-seq can be further optimized and expanded in spatial resolution and three-dimensional tissue analysis, and can be compatible with more omics information, and develop better spatial multiomics gene regulatory network analysis tools based on this, so as to reveal the specific mechanisms that drive cell identity and function determination in complex tissues.” Peng Guangdun said. (Source: China Science News, Zhu Hanbin, Hu Bingxin)

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