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Journal Article

Unblending of Transcriptional Condensates in Human Repeat Expansion Disease

MPS-Authors
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Basu,  Shaon
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mackowiak,  Sebastian
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Niskanen,  Henri
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Knezevic,  Dora
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Asimi,  Vahid
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Grosswendt,  Stefanie
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Ali,  Salaheddine
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Jerković,  Ivana
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos,  Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meissner,  Alexander
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Ibrahim,  Daniel M.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hnisz,  Denes
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Basu, S., Mackowiak, S., Niskanen, H., Knezevic, D., Asimi, V., Grosswendt, S., et al. (2020). Unblending of Transcriptional Condensates in Human Repeat Expansion Disease. Cell, 181(5): e30, pp. 1062-1079. doi:10.1016/j.cell.2020.04.018.


Cite as: https://hdl.handle.net/21.11116/0000-0006-8466-2
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.