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TAD boundaries and gene activity are uncoupled.
Faisal Almansour1, Nadezda A Fursova2, Adib Keikhosravi3
1Cell Biology of Genomes Group, National Cancer Institute, NIH, Bethesda MD 20892, USA.
Biorxiv : the Preprint Server for Biology
|December 25, 2025
Summary
Topologically associating domains (TADs) are key genome structures. Our study reveals TAD boundary architecture is uncoupled from gene activity, challenging their proposed role in gene regulation.
Area of Science:
- Genomics
- Epigenetics
- Molecular Biology
Background:
- Topologically associating domains (TADs) are fundamental units of genome organization.
- A proposed function of TADs is to regulate gene expression by controlling chromatin interactions.
Purpose of the Study:
- To investigate the relationship between TAD boundary architecture and gene activity.
- To determine if TADs play a direct role in gene regulation at the single-cell level.
Main Methods:
- High-throughput imaging to assess TAD boundary architecture and gene activity simultaneously.
- Single-cell and single-allele analysis.
- Depletion of the CTCF protein to disrupt TAD boundaries.
Main Results:
- TAD boundaries exhibit more frequent pairing than non-boundary regions, but these interactions are infrequent.
- TAD boundary proximity is uncorrelated with transcriptional activity within TADs.
- Disrupting TAD boundaries via CTCF depletion does not affect gene expression within TADs.
Conclusions:
- TAD boundary architecture and gene activity appear to be largely uncoupled.
- The proposed model of TADs directly regulating gene expression through boundary interactions requires re-evaluation.
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