Abstract 4146868: Mapping 3’ untranslated regions reveal compromised alternative polyadenylation in human right ventricle failure

Background: Right ventricular failure (RVF) impacts the prognosis of pulmonary arterial hypertension (PAH). Alternative polyadenylation (APA) generates transcript diversity and is implicated in diseases, including left heart failure. However, understanding genome-wide polyadenylation maps in RVF patients with PAH is limited, with no studies investigating RVF-specific APA events. Objective: This study mapped 3' untranslated regions (3'UTRs) to explore APA dynamics in RVF development, comparing healthy donors and RVF from patients with PAH. Methods and Results: RV tissues were obtained from patients with failing RV from heart and double lung transplant recipients. Poly(A)-ClickSeq (PAC-seq) RNA sequencing and PolyA-miner algorithm were used. Analysis revealed significant changes in cleavage site usage, identifying 690 genes with altered APA patterns in RVF. Notably, our investigation uncovered a significant finding related to CPSF6, a key factor involved in APA regulation. We observed a substantial lengthening of the 3'UTR in CPSF6, suggesting disrupted polyadenylation events in RVF. Intriguingly, this lengthening coincided with a noticeable decrease in CPSF6 protein levels, indicating a potential regulatory mechanism affecting its expression. Additionally, 530 genes had shortened 3'UTRs enriched for RNA binding and hypertrophic cardiomyopathy pathways, while 160 genes had lengthened 3'UTRs enriched for RNA surveillance and ribosomal RNA binding. Disease-specific APA signatures in RVF patients with PAH were identified. Conclusion: The present study highlights the significant role of APA in human RVF exerting its influence on multiple pathways and regulating specific gene expression. These findings offer insights into RVF in PAH patients and may guide the identification of therapeutic targets and strategies for improved management of the condition.