Single-cell epigenomic variability reveals functional cancer heterogeneity.

Area of Science:

• Cancer Biology
• Epigenetics
• Single-cell Analysis

Background:

• Cell-to-cell heterogeneity drives cancer evolution, progression, and drug resistance.
• Single-cell epigenomic variation is a key source of this heterogeneity but is challenging to study functionally.
• Detecting and understanding functional consequences of epigenomic changes at the single-cell level is crucial.

Purpose of the Study:

• To develop a method linking single-cell epigenomic measurements to functional outcomes.
• To identify markers and mechanisms driving cancer cell heterogeneity.
• To bridge the gap between epigenomic measurement and functional assessment in cancer.

Main Methods:

• Single-cell chromatin accessibility and RNA-sequencing were performed on K562 leukemic cells.
• Cell surface marker CD24 was identified as co-varying with chromatin accessibility and GATA transcription factor levels.
• Fluorescence-activated cell sorting (FACS) was used to prospectively isolate cell subpopulations based on CD24 expression.

Main Results:

• CD24 expression levels prospectively isolated cells with high versus low GATA1 and GATA2 levels.
• GATA-expressing subpopulations exhibited distinct gene regulatory networks and differential sensitivity to imatinib mesylate.
• Lineage tracing demonstrated that GATA/CD24 high cells could rapidly reconstitute the heterogeneity of the original population, indicating functional epigenomic plasticity.

Conclusions:

• Single-cell chromatin accessibility analysis can guide the prospective isolation and characterization of cancer subpopulations.
• Epigenomic subpopulations significantly influence cancer drug sensitivity and clonal dynamics.
• Understanding epigenomic plasticity is key to addressing cancer evolution and therapeutic resistance.