Cleavage stimulating factor 64 depletion mitigates cardiac fibrosis through alternative polyadenylation

Alternative polyadenylation (APA) regulates gene expression by cleavage and addition of poly(A) sequence at different polyadenylation sites (PAS) in 3'UTR, thus, generating transcript isoforms with different lengths. Cleavage stimulating factor 64 (CstF64) is an APA regulator which plays a role in PAS selection and determines the length of 3'UTR. CstF64 favors the use of proximal PAS, resulting in 3'UTR shortening, which enhances the protein expression by increasing the stability of the target genes. The aim of this study is to investigate the role of CstF64 in cardiac fibrosis, a key event leading to heart failure (HF). We determined the expression of CstF64, key profibrotic genes, and their 3'UTR changes by calculating distal PAS (dPAS) usage in left ventricular (LV) tissues and cardiac fibroblasts from HF patients. CstF64 was upregulated in HF LV tissues and cardiac fibroblasts along with increased deposition of fibrosis genes such as COL1A and FN1 and significant shortening in their 3'UTR. In addition, HF cardiac fibroblasts showed increased transforming growth factor receptor b1 (TGFbR1) expression consistent with significant shortening in 3'UTR of TGFbR1. Upon knockdown of CstF64 from HF fibroblasts, downregulation in pro-fibrotic genes corresponding to lengthening in their 3'UTR was observed. Our finding suggests an important role of CstF64 in myofibroblast activation and promotion of cardiac fibrosis during HF through APA. Therefore, targeting CstF64 mediated RNA processing approach in human HF could provide a new therapeutic treatment strategy for limiting fibrotic remodeling. (c) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study investigates the role of CstF64 in cardiac fibrosis and finds that CstF64 is upregulated in the heart tissues and cardiac fibroblasts of heart failure patients, leading to increased fibrosis gene expression and significant shortening of the 3'UTR. Knockdown of CstF64 results in downregulation of fibrotic genes and lengthening of the 3'UTR. These findings suggest that CstF64 plays an important role in myofibroblast activation and cardiac fibrosis during heart failure.