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  Unblending of Transcriptional Condensates in Human Repeat Expansion Disease

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-8466-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-8467-1
Genre: Journal Article

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 Creators:
Basu, Shaon1, Author              
Mackowiak, Sebastian1, Author              
Niskanen, Henri1, Author              
Knezevic, Dora1, Author              
Asimi, Vahid1, Author              
Grosswendt, Stefanie2, Author              
Geertsema, Hylkje , Author
Ali, Salaheddine3, Author              
Jerković, Ivana 3, Author
Ewers, Helge , Author
Mundlos, Stefan3, Author              
Meissner, Alexander2, Author              
Ibrahim, Daniel M.3, Author              
Hnisz, Denes1, Author              
Affiliations:
1Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014188              
2Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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

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Language(s): eng - English
 Dates: 2020-04-132020-05-072020-05-28
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.cell.2020.04.018
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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 181 (5) Sequence Number: e30 Start / End Page: 1062 - 1079 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183