Cleavage stimulating factor 64 depletion mitigates cardiac fibrosis through alternative polyadenylation.
3′UTR
Alternative polyadenylation
Fibrosis
Heart failure
Myofibroblast
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
15 Mar 2022
15 Mar 2022
Historique:
received:
28
12
2021
accepted:
24
01
2022
medline:
9
2
2022
pubmed:
9
2
2022
entrez:
8
2
2022
Statut:
ppublish
Résumé
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 β1 (TGFβR1) expression consistent with significant shortening in 3'UTR of TGFβR1. 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.
Identifiants
pubmed: 35134608
pii: S0006-291X(22)00120-6
doi: 10.1016/j.bbrc.2022.01.093
pmc: PMC9334457
mid: NIHMS1778123
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
109-114Subventions
Organisme : NIA NIH HHS
ID : R01 AG059599
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138510
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest There are no conflicts of interest.
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