2. Academic Validation
  3. Unblending of Transcriptional Condensates in Human Repeat Expansion Disease

Unblending of Transcriptional Condensates in Human Repeat Expansion Disease

  • Cell. 2020 May 28;181(5):1062-1079.e30. doi: 10.1016/j.cell.2020.04.018.
Shaon Basu 1,  Sebastian D Mackowiak 1,  Henri Niskanen 1,  Dora Knezevic 1,  Vahid Asimi 1,  Stefanie Grosswendt 1,  Hylkje Geertsema 2,  Salaheddine Ali 3,  Ivana Jerković 4,  Helge Ewers 2,  Stefan Mundlos 3,  Alexander Meissner 5,  Daniel M Ibrahim 3,  Denes Hnisz 6
Affiliations

Affiliations

  • 1 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 2 Institute for Chemistry and Biochemistry, Free University Berlin, 14195 Berlin, Germany.
  • 3 RG Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Charité-Universitätsmedizin Berlin, BCRT-Berlin Institute of Health Center for Regenerative Therapies, 10178 Berlin, Germany.
  • 4 RG Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 5 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • 6 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. Electronic address: [email protected].
PMID: 32386547 DOI: 10.1016/j.cell.2020.04.018
Abstract

Expansions of amino acid repeats occur in >20 inherited human disorders, and many occur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Such diseases are associated with protein aggregation, but the contribution of aggregates to pathology has been controversial. Here, we report that alanine repeat expansions in the HOXD13 TF, which cause hereditary synpolydactyly in humans, alter its phase separation capacity and its capacity to co-condense with transcriptional co-activators. HOXD13 repeat expansions perturb the composition of HOXD13-containing condensates in vitro and in vivo and alter the transcriptional program in a cell-specific manner in a mouse model of synpolydactyly. Disease-associated repeat expansions in other TFs (HOXA13, RUNX2, and TBP) were similarly found to alter their phase separation. These results suggest that unblending of transcriptional condensates may underlie human pathologies. We present a molecular classification of TF IDRs, which provides a framework to dissect TF function in diseases associated with transcriptional dysregulation.

Keywords

activation domain; condensate; intrinscially disordered region; phase separation; repeat expansion; synpolydactyly; transcription factor; transcriptional condensate.

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