Context-dependent RNA regulation and its application in auto-gating therapeutics for brain disorders

Neuronal gene regulation is spatiotemporally controlled in a highly context-dependent manner through combinatorial interactions of RNA binding proteins (RBPs). These interactions are typically mediated by the intrinsically disordered domains (IDRs) of RBPs and their multivalent binding to RNA. A key goal of biomedical research is to determine how multivalent assemblies of RBPs on primary transcripts enable selective and developmentally dynamic regulatory programmes, and how these programmes are disrupted in pathological contexts. A closely related goal is to exploit knowledge of these mechanisms to establish improved therapeutics for brain disorders that currently lack effective treatments. We will draw on our collective extensive expertise in the areas of RNA biology, genomics, and brain disorders, to: (a) understand mechanisms underlying the formation of ribonucleoprotein (RNP) assemblies that are critical for the spatiotemporal regulation of RNA processing and translation in cortical neurons; (b) systematically dissect mechanisms whereby mutations in brain disorder-relevant RBPs selectively perturb RNP assembly and function, and define the underlying sequence codes mediating this selectivity; and (c) develop combined transcriptional, RNA processing and localization modules for autonomously-gated gene therapeutic applications. Thus, through a new understanding of post-transcriptional gene regulation, we will develop context-dependent therapeutic strategies for brain disorders.