Context-dependent RNA regulation and its application in auto-gating therapeutics for brain disorders
Neuronal gene regulation is controlled in a highly spatiotemporal and context-dependent manner. This regulation is largely mediated by combinatorial assembly of many proteins on each RNA molecule.
The combinatorial assembly largely depends intrinsically disordered domains that can form many weak and dynamic interactions between proteins, thus stimulating their cooperative binding to many sites on RNA. Such assemblies recognise complex regulatory information and coordinate RNA processing, localization and translation.
A central challenge in biomedical research is to understand how such protein-RNA assemblies encode selective, developmentally dynamic regulatory programmes, and how disruption of these assemblies contributes to brain disorders. Mutations in proteins linked to neurodevelopmental and neurodegenerative conditions often perturb such assemblies, leading to disrupted RNA regulation.
Building on our expertise in studying RNA biology, genomics and brain disorders, this project will uncover the molecular principles governing the protein-RNA assemblies and leverage this knowledge to design context-dependent, autonomously gated gene therapeutic strategies for brain disorders.
External Collaborators
Oscar Wilkins, UCL
Aims
Define the mechanisms of protein-RNA assembly
- Elucidate how proteins and their disordered regions mediate combinatorial interactions to form functional assemblies on RNAs in cortical neurons.
Dissect disease-associated perturbations
- Systematically determine how mutations in the relevant proteins alter their assembly on RNAs and their regulatory selectivity.
Decode the regulatory sequence logic
- Identify RNA sequence and structural elements that specify selective protein recruitment and context-dependent impact of disease mutations.
Develop auto-gated therapeutic modules
- Engineer integrated transcriptional, RNA processing, and localization modules to enable context-dependent gene therapeutic applications.
Methods
- Molecular and cellular approaches to characterize protein–RNA interactions and their RNA assembly in cortical neurons.
- Genomic and transcriptomic profiling to map the composition of protein-RNA complexes and their impact on RNA processing and translational regulation under physiological and disease-relevant conditions.
- Mutational and structure–function analyses to define how the disordered regions in proteins and disease-associated variants alter protein-RNA assembly and function.
- Computational modelling to identify sequence codes governing selective RBP recruitment and regulatory specificity.
- Synthetic biology strategies to design and test autonomously gated transcriptional and post-transcriptional regulatory modules in neuronal systems.
Summary of Findings
This project will establish mechanistic principles explaining how protein-RNA assemblies generate context-dependent RNA regulatory programmes in neurons.
We expect to:
- Define molecular rules governing protein-RNA assembly and selectivity.
- Identify sequence determinants that encode regulatory specificity.
- Reveal how disease-associated mutations perturb the dynamics and function of protein-RNA complexes.
- Demonstrate proof-of-concept autonomously gated therapeutic modules informed by endogenous regulatory logic.
Impact
By advancing fundamental understanding of post-transcriptional gene regulation in neurons, this work will transform our understanding of how regulatory specificity is achieved in complex cellular contexts. It will thus provide a mechanistic foundation for developing next-generation, context-dependent gene therapeutics for brain disorders that currently lack effective treatments.
Principal Investigators
Professor of Developmental Neuroscience
Professor of RNA Biology and Genomics
Van Geest Professor of Neurodegeneration Research
Affiliations
Funding
Funding Body: Wellcome Trust
Amount: £5,443,308
Period: October 2024 - September 2032