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...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.展开更多
基金supported by research grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project(Nos.2024ZD0521500 and 2024ZD0521501,China)the National Natural Science Foundation of China(82270246,82070240,82470280 and 82300493)+1 种基金the Natural Science Foundation of Heilongjiang Province of China(JJ2024LH2446)China Postdoctoral Science Foundation(2023MD734169,China).
文摘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.
