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

  • Mol Cell. 2026 May 21;86(10):1911-1930.e11. doi: 10.1016/j.molcel.2026.04.019.
Ashley Karnay  1 ,  Ricardo Linares-Saldana  1 ,  Qiaohong Wang  1 ,  Zachary Gardner  1 ,  Jialiu A Liang  1 ,  Garrett T Santini  1 ,  Krishna Kumar Haridhasapavalan  1 ,  Son C Nguyen  2 ,  Siewert Hugelier  3 ,  Bhavana Shewale  4 ,  Masato T Kanemaki  5 ,  Jill S Napierala  6 ,  Marek Napierala  6 ,  Robert B Wilson  7 ,  Nicole Dubois  4 ,  Andrey Poleshko  1 ,  Wonho Kim  8 ,  Parisha P Shah  1 ,  Melike Lakadamyali  9 ,  Eric F Joyce  2 ,  Rajan Jain  10
Affiliations
  • 1. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2. Epigenetics Institute, Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4. Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 5. Department of Biological Sciences, Graduate School of Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Shizuoka 411-8540, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Mishima, Shizuoka 411-8540, Japan; Department of Biological Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 6. Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7. Department of Pathology and Laboratory Medicine, Penn/CHOP Center of Excellence for Friedreich's Ataxia Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 8. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 9. Epigenetics Institute, Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 10. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 42127908 DOI: 10.1016/j.molcel.2026.04.019
Abstract

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.

Keywords
3D spatial positioning; FXN; Friedreich’s ataxia; LADs; cohesion; disease; genome organization; hiPSC; plasticity; transcription.
Products