2. Academic Validation
  3. Correction of the molecular phenotype of X-linked Dystonia-Parkinsonism reveals a non-canonical function of BRD4

Correction of the molecular phenotype of X-linked Dystonia-Parkinsonism reveals a non-canonical function of BRD4

  • Nat Commun. 2026 May 5;17(1):4062. doi: 10.1038/s41467-026-72319-6.
Simona Capponi 1 2,  Sandra Ehret 1,  Zeynep Camgöz 1 2,  Fabian Gather 3,  Christine A Vaine 4 5,  Ezgi Özyerli-Göknar 1 2,  Marie Follo 6,  D Cristopher Bragg 4 5,  Tanja Vogel 3,  H Th Marc Timmers 7 8
Affiliations

Affiliations

  • 1 Department of Urology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 2 German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 3 Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
  • 4 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 5 Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
  • 6 Department of Medicine I, Lighthouse Core Facility, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 7 Department of Urology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].
  • 8 German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
PMID: 42086561 DOI: 10.1038/s41467-026-72319-6
Abstract

Transcription and mRNA processing are tightly coupled regulatory layers on gene expression, and their perturbations underly human disorders. X-linked Dystonia-Parkinsonism (XDP) is a unique example of a human disease connecting aberrant mRNA processing and the basal transcription machinery. XDP is a rare, monogenic fatal neurodegenerative disorder, and a limited understanding of the underlying molecular mechanisms hinders the development of effective therapies. In this study, we show that depletion of BRD4, a chromatin reader known for its role in transcriptional pausing, rescues the XDP molecular signature. Unexpectedly, this effect is independent of the canonical coactivator role of BRD4. We demonstrate that the XDP-SVA induces intronic premature cleavage and polyadenylation within the TAF1 locus, and that BRD4 depletion bypasses this premature termination checkpoint. These findings reveal new dimensions of BRD4 activity beyond transcription pause release and suggest modulation of mRNA processing as a therapeutic strategy for XDP.

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