Circulation research · 2025
Novel Truncated Peptide Derived From circCDYL Exacerbates Cardiac Hypertrophy.
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Li Mengyang, Ding Wei, Fang Xinyu, Wang Yu, Wang Peiyan, Ye Lin, Miao Shuo, Song Lin, Ao Xiang, Li Qi, Wang Jianxun
Аннотация
BACKGROUND: Circular RNAs (circRNAs) have been gradually revealed to regulate the progression of heart disease in depth, showing their clinical significance. However, a mass of cardiac circRNAs still has not been functionally characterized. We aimed to explore the potential candidates that are involved in pathological cardiac hypertrophy.
METHODS: Public substantial RNA-sequencing data of cardiac circRNAs were utilized to search the cardiac hypertrophy-related circRNAs. Cardiomyocyte hypertrophy in vitro was induced by Ang II (angiotensin II) treatment. Mice were subjected to Ang II infusion to induce cardiac hypertrophy in vivo. Gain-of-function and loss-of-function assays were conducted to detect the effect of RNAs or proteins in cardiac hypertrophy.
RESULTS: A circRNA derived from the cdyl (chromodomain Y-like) gene was screened out and named circCDYL. Our results showed that the expression of circCDYL in primary rat cardiomyocytes was significantly induced by Ang II. Gain-of-function and loss-of-function assays demonstrated that circCDYL effectively promoted cardiomyocyte hypertrophy in vitro. CircCDYL could encode a ≈100-aa truncated CDYL peptide (tCDYL-100), whose sequence highly overlaps that of full-length CDYL. The translation of tCDYL-100 was activated by N6-methylation of circCDYL under prohypertrophic stimulation. tCDYL-100 fulfilled the prohypertrophic function of circCDYL. Mechanistically, tCDYL-100 competed with CDYL for binding REST (RE1-silencing transcription factor) and further disrupted the formation of REST-CDYL-EHMT2 (euchromatic histone-lysine N-methyltransferase 2) transcriptional repression complex, resulting in transcriptional activation of rhoa and nppb. Silence of circCDYL in mouse hearts could inhibit Ang II-induced cardiac hypertrophy, while forced expression of tCDYL-100 could cause cardiac hypertrophy.
CONCLUSIONS: In summary, our study uncovered an important circRNA-derived peptide and a regulatory mechanism on transcription mediated by N6-methyladenosine-circRNA-histone methylation in pathological cardiac hypertrophy.
METHODS: Public substantial RNA-sequencing data of cardiac circRNAs were utilized to search the cardiac hypertrophy-related circRNAs. Cardiomyocyte hypertrophy in vitro was induced by Ang II (angiotensin II) treatment. Mice were subjected to Ang II infusion to induce cardiac hypertrophy in vivo. Gain-of-function and loss-of-function assays were conducted to detect the effect of RNAs or proteins in cardiac hypertrophy.
RESULTS: A circRNA derived from the cdyl (chromodomain Y-like) gene was screened out and named circCDYL. Our results showed that the expression of circCDYL in primary rat cardiomyocytes was significantly induced by Ang II. Gain-of-function and loss-of-function assays demonstrated that circCDYL effectively promoted cardiomyocyte hypertrophy in vitro. CircCDYL could encode a ≈100-aa truncated CDYL peptide (tCDYL-100), whose sequence highly overlaps that of full-length CDYL. The translation of tCDYL-100 was activated by N6-methylation of circCDYL under prohypertrophic stimulation. tCDYL-100 fulfilled the prohypertrophic function of circCDYL. Mechanistically, tCDYL-100 competed with CDYL for binding REST (RE1-silencing transcription factor) and further disrupted the formation of REST-CDYL-EHMT2 (euchromatic histone-lysine N-methyltransferase 2) transcriptional repression complex, resulting in transcriptional activation of rhoa and nppb. Silence of circCDYL in mouse hearts could inhibit Ang II-induced cardiac hypertrophy, while forced expression of tCDYL-100 could cause cardiac hypertrophy.
CONCLUSIONS: In summary, our study uncovered an important circRNA-derived peptide and a regulatory mechanism on transcription mediated by N6-methyladenosine-circRNA-histone methylation in pathological cardiac hypertrophy.