Decoding heterogeneous single-cell perturbation responses.

Area of Science:

• Cell Biology
• Genomics
• Bioinformatics

Background:

• Single-cell analysis is vital for understanding cellular heterogeneity.
• Existing methods struggle to accurately quantify diverse single-cell responses to perturbations.
• Interpreting gene function and cellular responses requires robust quantitative tools.

Purpose of the Study:

• To introduce a novel method, the perturbation-response score (PS), for quantifying single-cell responses to perturbations.
• To enable accurate analysis of partial gene perturbations and single-cell dosage effects.
• To identify gene-specific response patterns and uncover novel biological roles.

Main Methods:

• Development and application of the perturbation-response score (PS) method.
• Analysis of single-cell perturbation datasets (e.g., Perturb-seq).
• Comparative analysis against existing quantification methods.

Main Results:

• PS accurately quantifies diverse single-cell responses, outperforming existing methods for partial gene perturbations.
• PS enables single-cell dosage analysis without experimental titration.
• Identified 'buffered' and 'sensitive' response patterns for essential genes.
• Revealed differential cellular responses in T cell stimulation, HIV-1 expression, and pancreatic differentiation.
• Discovered a novel role for CCDC6 in liver and pancreatic cell fate regulation.

Conclusions:

• The perturbation-response score (PS) offers a powerful approach for dose-to-function analysis in single-cell perturbation studies.
• PS provides deeper insights into cellular responses and gene function.
• This method advances the quantitative analysis of complex biological systems at the single-cell level.