Tracking single-cell evolution using clock-like chromatin accessibility loci.

Area of Science:

• Genomics
• Developmental Biology
• Epigenetics

Background:

• Single-cell chromatin accessibility sequencing (scATAC-seq) is used for developmental trajectory reconstruction based on cell phenotypes.
• Inferring precise developmental trajectories remains a significant challenge in cell biology.
• Age-associated DNA methylation (DNAm) changes occur at specific genomic regions, known as clock-like differential methylation loci (ClockDML).

Purpose of the Study:

• To develop a novel method, EpiTrace, for determining cell age and performing lineage tracing using scATAC-seq data.
• To leverage the reduced heterogeneity of chromatin accessibility at clock-like loci after cell division as a measure of mitotic age.
• To validate EpiTrace's concordance with established developmental hierarchies and other lineage tracing methods.

Main Methods:

• Developed EpiTrace, a computational method analyzing scATAC-seq data.
• Quantified the fraction of opened clock-like loci to infer cell age.
• Applied EpiTrace across diverse cell lineages and species, including hematopoiesis, organ development, and tumor biology.

Main Results:

• EpiTrace successfully determines cell age and reconstructs developmental trajectories.
• The method shows strong concordance with known developmental hierarchies.
• Results correlate well with DNA methylation-based clocks and complement other lineage tracing techniques like mutation-based tracing and RNA velocity.

Conclusions:

• EpiTrace provides a robust tool for cell age determination and lineage tracing using scATAC-seq.
• The method offers valuable biological insights with potential clinical relevance in areas such as development, immunity, and cancer.
• EpiTrace enhances our understanding of cellular processes by integrating epigenetic and chromatin accessibility data.