Reduction of negative regulatory activity is predicted to underlie neurotrophin-driven APA. (A–D) Distribution of Fisher's enrichment scores (−log10(P-value)) in cross-link events of 126 RBPs along the short 3′ UTR isoforms of the pairs of isoforms showing significant promoter-proximal shifts in NTF3 (A) or NGF (B) and promoter-distal shifts in NTF3 (C) or NGF (D). (E–H) Networks of protein–protein interactions for the RBPs showing significant enrichment in cross-link events in the [0:+150]-nt regions downstream from the 3′ end of the short 3′ UTR isoforms associated with significant promoter-proximal shifts in NTF3 (A) or NGF (B) and promoter-distal shifts in NTF3 (C) or NGF (D). Edges represent experimentally determined protein–protein interactions annotated in the STRING database. Nodes indicate proteins colored according to the biological pathways they are enriched in. Arrows indicate the predicted directions in changes in activity of the RBPs. (I–L) Genome browser views of 3′ end sequencing profiles and CLIP cross-linking events for predicted positive (green) and negative (gold) regulators of APA for 3′ UTR isoforms showing a marked shift toward increase in promoter-proximal 3′ UTR usage (Rbm41 and Slc39a13) or in promoter-distal 3′ UTR usage (Usp15 and Ppfia4) in either condition. Gray boxes highlight the location of promoter-proximal and promoter-distal 3′ UTR isoforms.
