Emerging Principles in Spatial Functional Genomics

Area of Science:

• Genomics
• Systems Biology
• Bioinformatics

Background:

• Spatial atlases map gene programs in tissues but lack mechanistic insight.
• Pooled CRISPR screening offers causal gene function insights but loses spatial context.
• Bridging these gaps is crucial for understanding tissue biology mechanisms.

Purpose of the Study:

• To introduce and outline the design principles of in vivo spatial functional genomics (SFG).
• To demonstrate SFG's capability in measuring gene function within intact tissue ecosystems.
• To highlight SFG's potential for revealing context-dependent gene functions.

Main Methods:

• Integrating pooled CRISPR screening with in situ spatial transcriptomics and proteomics.
• Preserving tissue architecture to analyze gene perturbation effects.
• Developing computational methods for spatial autocorrelation and neighborhood dependence.

Main Results:

• SFG enables causal interrogation of gene function within the spatial context of tissues.
• Perturbations can be interpreted through effects on cell-cell interactions and tissue architecture.
• SFG reveals non-cell-autonomous and architecture-dependent mechanisms of gene function.

Conclusions:

• SFG provides a powerful framework for dissecting gene function in its native tissue environment.
• This approach advances the development of predictive models for tissue organization.
• SFG bridges the gap between descriptive spatial atlases and mechanistic understanding of tissue biology.