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Unblending of transcriptional condensates in human repeat expansion disease

Item Type:Article
Title:Unblending of transcriptional condensates in human repeat expansion disease
Creators Name:Basu, S. and Mackowiak, S.D. and Niskanen, H. and Knezevic, D. and Asimi, V. and Grosswendt, S. and Geertsema, H. and Ali, S. and Jerković, I. and Ewers, H. and Mundlos, S. and Meissner, A. and Ibrahim, D.M. and Hnisz, D.
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:Transcription Factor, Phase Separation, Condensate, Transcriptional Condensate, Repeat Expansion, Synpolydactyly, Intrinscially Disordered Region, Activation Domain, Animals, Mice
Publisher:Cell Press
Page Range:1062-1079
Date:28 May 2020
Official Publication:https://doi.org/10.1016/j.cell.2020.04.018
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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