Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits

Abstract

29We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated 30 with intellectual disability (Gennarino et al., 2015). However, the patients' CNVs also included 31 other genes. To determine if reduced NUDT21 function alone can cause disease, we generated 32 Nudt21 +/mice to mimic the human state of decreased expression. We found that although these 33 mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. 34Despite this partial protein-level compensation, the Nudt21 +/mice have learning deficits and 35 cortical hyperexcitability. Further, to determine the molecular mechanism driving neural 36 dysfunction, we partially inhibited NUDT21 in human stem cell-derived neurons to reduce 37 CFIm25 by 30%. This reduction in CFIm25 was sufficient to induce misregulated alternative 38 polyadenylation (APA) and protein levels in hundreds of genes, dozens of which cause 39 intellectual disability when mutated. Altogether, these results indicate that disruption of 40

PolyAMiner-Bulk: A Machine Learning Based Bioinformatics Algorithm to Infer and Decode Alternative Polyadenylation Dynamics from bulk RNA-seq data

“…These discordant findings likely reflect feedback interactions like post-transcriptional regulation that maintain protein homeostasis, consistent with findings that transcript-protein concordance varies among coregulated gene sets. In another study, we observed 3’UTR shortening of mRNA isoforms strongly correlating with increased levels of corresponding proteins in murine neurodegenerative models (58). This finding suggests that APA may partly explain this transcriptome-proteome discordance, implicating AD as a prime disease-of-interest to investigate further with PolyAMiner-Bulk.…”