Developing an epitranscriptional palette of writers to record and shape RNA fate

Objetivo

While DNA-targeting tools like CRISPR have revolutionized our ability to interrogate and engineer biology, analogous platforms for RNA remain underdeveloped, despite the unique potential offered by RNA given its transient, non-integrative, and programmable nature. We here propose to bridge this gap by exploiting the power of RNA-modification enzymes (RMEs), collectively responsible for adding >170 chemical marks to RNA molecules (the ‘epitranscriptome’), and thereby tune folding, stability, localization, translation and protein binding. Building on our strong preliminary results, we will (1) establish an expanded palette of programmable RMEs that “write” RNA modifications in vivo, either globally or site-specifically; (2) develop combinatorial molecular recorders that chemically encode interactions between individual mRNA transcripts and distinct RNA-binding proteins across cellular compartments, allowing to reconstruct single-transcript molecular histories; and (3) dissect the impact of RNA modifications on translation and harness site-specific RMEs to reprogram translation and correct pathogenic variants. This project will transform our ability to track, perturb, and manipulate the RNA life cycle, and give rise to new tools, biological insights and therapeutic avenues. This integrated strategy will convert the epitranscriptome from an observational landscape into an engineerable dimension of molecular regulation and recording —enabling combinatorial, quantitative molecular recording and precision reprogramming of the genetic code, with far-reaching applications in basic biology, synthetic biology, and RNA-based therapies.

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