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bioRxiv · 10.1101/2025.09.29.679194

Target-site Dynamics and Alternative Polyadenylation Explain Large Share of Apparent MicroRNA Differential Expression

Cihan, M.·More, P.·Sprang, M.·Marini, F.·Andrade, M.
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Abstract

MicroRNA (miRNA) abundance reflects a dynamic balance between biogenesis, target engagement, and decay, yet differential expression analyses typically ignore changes in target-site availability driven by alternative polyadenylation (APA). We introduce MIRNAPEX, an expression-stratification-based machine learning framework that quantifies miRNA regulatory effect sizes from RNA-seq data by integrating target-gene expression with 3'UTR isoform usage to infer effective binding-site dosage. Using pan-cancer training sets, we train models that learn relationships between transcriptomic features and miRNA log-fold changes, with APA patterns providing predictive information beyond gene expression alone. When applied to knockdowns of core APA regulators, MIRNAPEX captured widespread 3'UTR shortening and accurately anticipated miRNA-specific shifts whose direction and magnitude mirrored APA-driven changes in binding-site availability. Analysis of target-directed miRNA degradation interactions further showed that loss of distal decay-trigger sites coincides with increased miRNA abundance, consistent with reduced degradation. Together, these findings demonstrate that apparent miRNA differential expression can arise from dynamic target-site landscapes rather than altered miRNA transcription, and that neglecting this dimension can lead to misestimation of regulatory effect sizes.

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Cihan, M., More, P., Sprang, M., Marini, F., Andrade, M.. 2025-10-01. Target-site Dynamics and Alternative Polyadenylation Explain Large Share of Apparent MicroRNA Differential Expression. https://doi.org/10.1101/2025.09.29.679194

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