Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability.

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Genome integrity is crucial for multicellular organisms.
• DNA damage from endogenous and environmental factors is a constant threat.
• Analyzing DNA damage consequences is challenging due to complex cell compositions and stochastic damage.

Purpose of the Study:

• To develop a method for joint analysis of DNA damage and gene expression in single cells.
• To investigate the genomic distribution and functional consequences of DNA damage.
• To understand cell-type-specific patterns of DNA damage and their link to disease.

Main Methods:

• Developed Paired-Damage-seq for simultaneous analysis of oxidative and single-stranded DNA damage with gene expression.
• Applied the method to cultured HeLa cells and the mouse brain.
• Analyzed associations between DNA damage, epigenetic changes, and gene expression.

Main Results:

• Paired-Damage-seq enables joint analysis of DNA damage and gene expression at the single-cell level.
• Identified associations between DNA damage formation and epigenetic modifications.
• Observed cell-type-specific patterns in oxidative DNA damage hotspots.
• Demonstrated that damage distribution can predict cell types and dysregulated molecular programs.

Conclusions:

• The new method overcomes challenges in studying DNA damage in complex tissues.
• Cell-type-specific vulnerability to DNA damage influences molecular programs and disease risk.
• This approach provides insights into genome maintenance and disease mechanisms.