Intermolecular 3'UTR-3'UTR interactions drive Wnt gene activation through heteromeric protein assembly
Cai, T.; Cruz, N. M.; Basu, S.; White, R. M.; Mayr, C.
Show abstract
Stem cell differentiation depends on transcription factors that are often encoded by mRNAs with highly conserved 3'UTRs. 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 {beta}-catenin, keeps {beta}-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 {beta}-catenin. As antisense oligonucleotide-mediated blocking of 3'UTR interactions impairs Wnt program induction, our findings indicate that transcriptional regulators can form functional units during protein biogenesis to be fully active.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.