Research & Initiatives

Decoding the molecular rules that control RNA fate

The Zaccara Lab investigates how RNA fate is encoded, regulated, and rewired in disease. We combine quantitative RNA biology, functional genomics, genome engineering, and proteomic technologies to discover regulatory mechanisms at nucleotide, protein-residue, and cellular resolution.

RNA molecules carry regulatory information beyond their primary sequence. We investigate how RNA modifications control RNA stability, processing, and translation, and how these regulatory programs are altered during disease.

We combine quantitative, nucleotide-resolution RNA profiling with direct RNA sequencing, functional genomics, and targeted perturbation to move beyond descriptive maps and determine which regulatory events have functional consequences.

1. How is RNA fate encoded and rewired in disease?

Schematic of the m6A mRNA life cycle,
adapted from Zaccara S et al., Nat Rev Mol Cell Biol. 2019 PMID: 31520073.

A major focus of the lab is understanding how RNA regulation is remodeled in hematologic disease, including myelodysplastic syndromes, T-cell lymphoma, and leukemia.

By integrating molecular mapping with perturbation and cellular phenotyping, we aim to distinguish changes that simply accompany disease from those that actively shape disease-associated cell states and create potential therapeutic vulnerabilities.

Schematic of our approach

2. How are RNA regulatory proteins themselves regulated?

RNA-binding proteins often rely on intrinsically disordered regions (IDRs) to control protein interactions, localization, and RNA fate, yet the contribution of individual residues remains poorly understood.

We use CRISPR base-editing screens and quantitative molecular assays to study these proteins at single-amino-acid resolution. Using the m6A reader YTHDF2 as a model, we identified residues within its disordered region that alter protein interactions, condensate recruitment, and m6A-dependent RNA decay.

We are now asking whether these residues can be used as molecular switches and whether the same strategy can uncover general rules governing other RNA-binding proteins.

40% of the proteins have an IDR; we still do not understand their grammar and function

Banani SF, Lee HO, Hyman AA, Rosen MK, Nature Reviews Molecular Cell Biology. 2017

Banani SF, et al., Developmental Cell, 2022

Results of our base editor screen for YTHDF2.

Ricci et al., bioRxiv 2026.09.18.752746;

3. How do protein complexes and cellular organization control RNA fate?

RNA fate is determined by dynamic networks of RNA-binding proteins, regulatory complexes, and subcellular compartments. We study how these molecular assemblies form, how they recognize and regulate specific RNAs, and how their organization changes across cellular states.

A major focus of the lab is identifying the protein complexes that control RNA stability and decay and understanding how individual RNA-binding proteins are incorporated into competing regulatory networks.

To study these interactions in their native cellular environment, we are developing proximity-labeling platform that maps endogenous protein-protein and protein-RNA neighborhoods without requiring overexpression. By combining interaction mapping with functional perturbation, we aim to define how molecular complexes and cellular organization determine RNA fate.

Tools & Technologies