A novel feedback loop: CELF1/circ-CELF1/BRPF3/KAT7 in 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.