Sequential-GAM constructs the single-cell geometric 3D genome structure

Area of Science:

• Genomics
• Cell Biology
• Structural Biology

Background:

• The 3D organization of chromatin is vital for cellular identity and gene regulation.
• Understanding the genome-wide hierarchical geometric structure within single cells remains a challenge.

Purpose of the Study:

• To develop a method for constructing the hierarchical geometric structure of the genome in single cells.
• To estimate the radial positioning of genomic elements and their relationship with gene expression.

Main Methods:

• Developed Sequential Genome Architecture Mapping (Sequential-GAM) to capture contiguous thin sections of the nucleus.
• Estimated radial positions of chromosomes, compartments, subcompartments, and genes.
• Defined quasi-stable topologically associating domains (q-stable TADs) to analyze structural stability.

Main Results:

• Identified radial gradients of epigenomic features and subcompartments from the nuclear center to periphery.
• Revealed dynamic radial positioning of B1 and B2 subcompartments.
• Found a correlation between chromatin structure stability and transcription activity.
• Demonstrated a negative correlation between gene radial distance/positional stability and gene expression.

Conclusions:

• Sequential-GAM enables the estimation of single-cell 3D genome structure, stability, and inter-cell heterogeneity.
• Chromatin's hierarchical organization and dynamic positioning are linked to gene regulation and cell identity.