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Published on: June 14, 2016
A novel feedback loop: CELF1/circ-CELF1/BRPF3/KAT7 in cardiac fibrosis
Yuan Jiang1,2,3, Bowen Zhang1,2,4, Bo Zhang1,2
1State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Insights
Circular RNA CELF1 (circ-CELF1) exacerbates cardiac fibrosis by promoting fibroblast proliferation and stabilizing BRPF3. This establishes a novel feedback loop, identifying circ-CELF1 as a potential therapeutic target for cardiac fibrosis.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Cardiac fibrosis, marked by excessive extracellular matrix, impairs heart function.
- Circular RNAs (circRNAs) are increasingly recognized as key regulators in cardiac fibrosis.
- Understanding the specific roles of circRNAs is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the functional role of circular RNA CELF1 (circ-CELF1) in cardiac fibrosis.
- To elucidate the molecular mechanisms underlying circ-CELF1's regulation of cardiac fibrosis.
- To identify a novel feedback loop involving circ-CELF1 in cardiac fibrosis.
Main Methods:
- Assessed the impact of circ-CELF1 on fibrosis markers and cardiac fibroblast proliferation.
- Investigated the interaction between circ-CELF1, BRPF3, and KAT7 using molecular assays.
- Analyzed the regulatory effects on Celf1 gene transcription and H3K14 acetylation.
- Examined the feedback loop mechanism for circ-CELF1 production.
Main Results:
- Circ-CELF1 significantly enhanced fibrosis markers and cardiac fibroblast proliferation.
- Circ-CELF1 stabilized BRPF3 by reducing its ubiquitination and degradation.
- BRPF3 recruited KAT7, leading to increased H3K14 acetylation at the Celf1 promoter, boosting Celf1 transcription.
- A positive feedback loop was identified where CELF1/circ-CELF1 promotes circ-CELF1 production.
Conclusions:
- Circ-CELF1 plays a critical role in promoting cardiac fibrosis through a novel feedback loop involving BRPF3 and KAT7.
- This feedback loop enhances CELF1 transcription and circ-CELF1 production, exacerbating fibrosis.
- Circ-CELF1 represents a promising therapeutic target for treating cardiac fibrosis.
Abstract:
Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.
