TAD Evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function

Area of Science:

• Genomics
• Evolutionary Biology
• Epigenetics

Background:

• Topological associating domains (TADs) are essential genomic structures that regulate gene expression.
• The evolutionary conservation and functional significance of TADs and their boundaries are not well understood.

Approach:

• Generated Hi-C and ChIP-seq data to compare TAD organization across four primate and four rodent species.
• Characterized genetic and epigenetic properties of TAD boundaries in relation to their evolutionary conservation.
• Utilized CRISPR-Cas9 to investigate the functional impact of ultraconserved and species-specific TAD boundaries in mouse models.

Key Points:

• Only 14% of human TAD boundaries are ultraconserved across all eight species studied; 15% are human-specific.
• Ultraconserved TAD boundaries exhibit stronger insulation, CTCF binding, and enrichment of older retrotransposons compared to species-specific boundaries.
• CRISPR-Cas9 disruption of ultraconserved boundaries caused tissue-specific gene expression changes and morphological phenotypes in mice.

Conclusions:

• TAD boundary evolution is extensive, with a significant proportion being species-specific.
• Ultraconserved TAD boundaries possess distinct molecular features and play critical roles in maintaining gene regulation and organismal development.
• The evolution of TADs contributes to species-specific gene regulation and phenotypic differences, with implications for diseases like autism.