Transcription and Cohesin Direct Genome Positioning and Domain Boundary Plasticity

Spatial positioning of the genome and cellular identity have been correlated, but the mechanistic principles underlying 3D genome organization remain unclear. Consequently, our understanding of how compromised genome positioning leads to disease are limited. Here, we demonstrate that a cooperative relationship between gene transcription and cohesin activity directs lamina-associated domain (LAD) boundary plasticity and boundary-proximal gene spatial positioning. Transcription mediates LAD boundary fidelity and loss of transcription repositions LAD-boundary genes to the nuclear lamina. The transcriptional repression-mediated repositioning is dependent on cohesin’s loop extrusion activity and cannot be linked to heterochromatin modifiers or compaction status. Further, pathogenic transcriptional silencing of the LAD-boundary gene FXN in Friedrich’s Ataxia is associated with improper peripheral positioning of FXN. Strikingly, loss of cohesin activity is sufficient to reposition mutant FXN away from the nuclear periphery and partially restore FXN transcription. Taken together, we reveal how molecular regulators of distinct genome organization processes collaboratively orchestrate LAD boundary plasticity.