Abstract 17448: Comprehensive Characterization of Alternative Polyadenylation in Human Right Ventricle Failure

Abstract

Background: Alternative cleavage and polyadenylation (APA) an emerging post-transcriptional mechanism for gene regulation that generates distinct isoforms of mRNA with different 3’UTR lengths. APA plays an important role in different biological processes and dysregulation of APA leading to many human diseases. However, the functional consequences of APA events in the right ventricle (RV) failure in humans remain unexplored. Objective: To identify whether the 3′UTR length is modulated by APA in the RV failure in humans compared to healthy RV. Methods and Results: We used Poly A tail RNA sequencing and a novel algorithm called DaPars to measure the global patterns of APA in healthy and failing human RV specimens. We revealed 3'UTR shortening and lengthening of many genes in failing RV compared to healthy RV specimens. The lengthened 3’UTR genes were enriched for functional groups such as RNA processing and splicing. Whereas the shortened 3’UTR genes were enriched for nucleic acid metabolic process and chromatin organization. In addition, differential APA events in RV failure regulates many pathways important for the progression of the RV failure. Finally, the regulator proteins of APA including cleavage and polyadenylation specificity factor (CPSF) 6 and 7, cleavage factor Im (CFIm) 25 and 59 have been regulated in RV failure compared to healthy RV specimens. Conclusions: Our results highlight important roles of APA in the progression of RV failure in humans, including RNA processing, splicing, and specific gene expression. Demonstrating that APA mediated 3’UTR length regulation provides the additional layer of gene expressions in RV failure.