Long-range interactions between topologically associating domains shape the four-dimensional genome during...

Area of Science:

• Genomics
• Molecular Biology
• Cell Biology

Background:

• Chromosomes are organized in the nucleus by interactions between topologically associating domains (TADs) and chromatin with the nuclear lamina.
• The combined role of these genomic organizers in shaping genome architecture during differentiation remains largely unknown.

Purpose of the Study:

• To investigate how TAD-TAD interactions and their relationship with lamina-associated domains contribute to genome organization during cell differentiation.

Main Methods:

• Utilized a dual-lineage differentiation system.
• Employed high-resolution chromosome conformation capture (Hi-C) in single-cell data.
• Analyzed dynamic changes during mouse embryonic stem cell differentiation and somatic cell reprogramming.

Main Results:

• Identified long-range TAD-TAD interactions forming constitutive and variable TAD cliques.
• Observed a differentiation-coupled relationship between TAD cliques and lamina-associated domains, suggesting heterochromatin stabilization at the nuclear periphery.
• Documented dynamic TAD cliques during differentiation and reprogramming, and inter-TAD associations in single-cell Hi-C data.

Conclusions:

• TAD cliques represent a novel level of four-dimensional genome conformation.
• These structures play a crucial role in stabilizing genome architecture and reinforcing the silencing of developmental genes during differentiation.