Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Understanding brain development and neuroinflammation requires mapping molecular changes in space and time.
• Existing technologies limit the ability to capture multi-omic information dynamically across brain regions.

Purpose of the Study:

• To develop and apply novel spatial tri-omic sequencing technologies for spatiotemporal brain mapping.
• To create a comprehensive spatiotemporal tri-omic atlas of the developing mouse brain.
• To investigate molecular mechanisms underlying brain development and neuroinflammation.

Main Methods:

• Developed and utilized DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq).
• Integrated spatial omics with multiplexed immunofluorescence imaging (CODEX).
• Generated a spatiotemporal tri-omic atlas from postnatal day P0 to P21 in mice and compared with human developing brains.

Main Results:

• Discovered temporal persistence and spatial spreading of chromatin accessibility for layer-defining transcription factors in the developing cortex.
• Observed dynamic chromatin priming of myelin genes in the corpus callosum, suggesting coordination between projection neurons, axonogenesis, and myelination.
• Identified common molecular programs in development and lysolecithin-induced (LPC) neuroinflammation, with microglia showing conserved and distinct responses.

Conclusions:

• Spatial tri-omic mapping provides insights into coordinated gene regulation during brain development.
• Common molecular pathways are involved in both brain development and neuroinflammation.
• The generated spatiotemporal tri-omic atlas is a valuable resource for studying brain function and disease.