期刊
CELL
卷 184, 期 18, 页码 4680-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.07.018
关键词
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资金
- MND Association (Lady Edith Wolfson Senior nonclinical fellowship) [Hallegger/Oct15/959-799]
- Wellcome Trust [103760/Z/14/Z, 215593/Z/19/Z, 110292/Z/15/Z, FC001110]
- PhD Training Fellowship for Clinicians Award [105202/Z/14/Z, 101149/Z/13/A]
- ERC [617837]
- European Union [835300]
- Francis Crick Institute (postdoctoral clinical fellowship)
- Target ALS, ALSA
- Robert Packard Center for ALS Research
- Office of the Assistant Secretary of Defense for Health Affairs (ALS Research Program) [W81XWH-20-1-024]
- BrightFocus Foundation (postdoctoral fellowship) [A2019612F]
- NINDS
- NIA [R01NS116176]
- Cancer Research UK [FC001110]
- UK Medical Research Council [FC001110]
- Wellcome Trust [215593/Z/19/Z, 105202/Z/14/Z, 101149/Z/13/A, 110292/Z/15/Z] Funding Source: Wellcome Trust
- European Research Council (ERC) [835300, 617837] Funding Source: European Research Council (ERC)
This study found that RBP condensation can selectively modulate transcriptome-wide RNA regulation in a binding-region-specific manner.
Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These binding-region condensates'' are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution.
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