Transcription and cohesin direct domain boundary spatial positioning and are linked to Friedreich's ataxia

Variability in genome organization drives differential gene expression and shapes cellular diversity, yet whether transcription actively instructs genome structure and how this relationship is exploited in disease remains unclear. We show that transcription and cohesin direct the spatial positioning of lamina-associated domain (LAD) boundary genes. Transcriptional repression repositions LAD boundary genes to the nuclear lamina in a cohesin loop extrusion-dependent manner. Conversely, overactive cohesin is sufficient to reposition and silence LAD boundary genes, an effect counteracted by maintaining transcription. In Friedreich's ataxia, we demonstrate improper positioning of the pathogenically repressed LAD boundary gene FRATAXIN (FXN) at the nuclear periphery reflects an imbalance between transcription and cohesin dynamics. Importantly, modulating either transcription or cohesin activity restores FXN positioning and reactivates expression. Our findings establish transcription and cohesin as tunable molecular rheostats orchestrating LAD boundary spatial positioning and reveal how the flexible and dynamic nature of genome architecture is hijacked in disease.