RNPdynamics | Multivalent interactions driving RNP dynamics in development and disease

Summary
Ribonucleoprotein complexes (RNPs) play many key regulatory roles in development. Moreover, mutations causing cancer or neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), often occur in RNA-binding proteins (RBPs). These mutations are concentrated in the intrinsically disordered regions (IDRs), which play a central role in the control of RNP assembly and disassembly. RNP dynamics is often driven by multivalent interactions that are mediated by multiple elements within IDRs of RBPs, which can condense the RNP such that it separates from the surrounding liquid through the phenomenon of liquid-liquid phase separation. Transcriptomic insights into the physiological functions of such multivalent RNP assembly are needed to understand their regulation, or deregulation through disease-causing mutations. Here, we will build a framework of experimental and computational methods to study the mechanisms by which the dynamic multivalent interactions drive RNP remodelling, and how such RNP dynamics contributes to cellular transitions in development and disease. The first objective will be to identify the functions of specific RBPs in cell-state transitions during neuronal differentiation, and the mechanisms of IDR-mediated multivalent interactions in these functions. The next objective will be to establish new tools to manipulate RNP assembly through multivalent RNA binding sites and IDRs. Finally, the new insights and tools will be integrated with the goal to fine-tune the RNP assembly of ALS-mutant RBPs, and thereby ameliorate their toxicity.
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More information & hyperlinks
Web resources: https://cordis.europa.eu/project/id/835300
Start date: 01-01-2020
End date: 30-09-2025
Total budget - Public funding: 2 396 261,25 Euro - 2 396 261,00 Euro
Cordis data

Original description

Ribonucleoprotein complexes (RNPs) play many key regulatory roles in development. Moreover, mutations causing cancer or neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), often occur in RNA-binding proteins (RBPs). These mutations are concentrated in the intrinsically disordered regions (IDRs), which play a central role in the control of RNP assembly and disassembly. RNP dynamics is often driven by multivalent interactions that are mediated by multiple elements within IDRs of RBPs, which can condense the RNP such that it separates from the surrounding liquid through the phenomenon of liquid-liquid phase separation. Transcriptomic insights into the physiological functions of such multivalent RNP assembly are needed to understand their regulation, or deregulation through disease-causing mutations. Here, we will build a framework of experimental and computational methods to study the mechanisms by which the dynamic multivalent interactions drive RNP remodelling, and how such RNP dynamics contributes to cellular transitions in development and disease. The first objective will be to identify the functions of specific RBPs in cell-state transitions during neuronal differentiation, and the mechanisms of IDR-mediated multivalent interactions in these functions. The next objective will be to establish new tools to manipulate RNP assembly through multivalent RNA binding sites and IDRs. Finally, the new insights and tools will be integrated with the goal to fine-tune the RNP assembly of ALS-mutant RBPs, and thereby ameliorate their toxicity.

Status

SIGNED

Call topic

ERC-2018-ADG

Update Date

27-04-2024
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Horizon 2020
H2020-EU.1. EXCELLENT SCIENCE
H2020-EU.1.1. EXCELLENT SCIENCE - European Research Council (ERC)
ERC-2018
ERC-2018-ADG