Identifying quantitatively differential chromosomal compartmentalization changes and their biological significance...

Area of Science:

• Genomics
• Computational Biology
• Epigenetics

Background:

• Chromosomal compartmentalization is crucial for cell differentiation and oncogenesis.
• Current comparative analyses of compartmentalization are limited to qualitative switched compartments.

Purpose of the Study:

• To develop a computational framework for identifying genomic regions with quantitatively differential compartmentalization changes from genome-wide chromatin conformation data.
• To analyze quantitative compartmentalization changes during human cardiomyocyte differentiation.
• To dissect the compartment variability landscape in the human genome.

Main Methods:

• Developed DARIC, a computational framework with modules for compartmentalization quantification, normalization, and differential analysis.
• Applied DARIC to Hi-C data for human cardiomyocyte differentiation.
• Analyzed a compendium of 32 Hi-C datasets from 4DN to study compartment variability.

Main Results:

• DARIC identified substantial genomic regions with significant quantitative compartmentalization changes, distinct from qualitative switching.
• These quantitative changes correlate with alterations in gene expression, chromatin accessibility, H3K27ac intensity, and nuclear lamina interactions.
• Dissected two distinct mechanisms for gene activation during cardiomyocyte differentiation and found a correlation between compartmentalization variability and sub-compartments.

Conclusions:

• DARIC is a valuable tool for analyzing quantitative compartmentalization changes and extracting biological insights from Hi-C data.
• Quantitative compartmentalization changes play a significant role in gene regulation.
• New insights into the relationship between compartmentalization variability and sub-compartments in the human genome were provided.