Intermolecular 3′UTR-3′UTR interactions drive Wnt gene activation through heteromeric protein assembly

To determine their functional roles, we performed 3′UTR loss-of-function studies. Partial deletion of endogenous 3′UTRs altered stem cell differentiation efficiency in 7/10 cases.

As 6/7 3′UTR deletions did not affect expression level of the encoded proteins, we reveal widespread abundance-independent regulatory roles of 3′UTRs. For example, 3′UTR deletion of CTNNB1, an mRNA that encodes the essential Wnt co-activator β-catenin, keeps β-catenin levels unaffected but impairs zebrafish embryogenesis and induction of the Wnt transcriptional program during human stem cell differentiation. We show that long intermolecular 3′UTR-3′UTR interactions between Wnt transcription factor mRNAs and CTNNB1 enable co-translational protein complex assembly of these transcription factors with β-catenin.