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Novel Truncated Peptide Derived From circCDYL Exacerbates Cardiac Hypertrophy
Mengyang Li1, Wei Ding2, Xinyu Fang2
1School of Basic Medicine (M.L., Y.W., P.W., L.Y., S.M., L.S., X.A., J.W.), Qingdao University, China.
Insights
This study identifies circCDYL as a key regulator in pathological cardiac hypertrophy. It encodes a peptide that promotes heart enlargement by disrupting gene repression complexes.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Epigenetics
Background:
- Circular RNAs (circRNAs) are increasingly recognized for their roles in heart disease.
- Many cardiac circRNAs remain functionally uncharacterized, necessitating further investigation.
- This study focuses on identifying novel circRNAs involved in pathological cardiac hypertrophy.
Purpose of the Study:
- To explore potential cardiac circRNA candidates involved in pathological cardiac hypertrophy.
- To elucidate the functional role and mechanism of identified circRNAs in cardiac hypertrophy.
Main Methods:
- Utilized RNA-sequencing data to identify cardiac hypertrophy-related circRNAs.
- Induced cardiomyocyte hypertrophy in vitro using Ang II and in vivo in mice.
- Performed gain-of-function and loss-of-function assays to assess RNA and protein effects.
Main Results:
- Identified circCDYL, significantly induced by Ang II in cardiomyocytes, promoting hypertrophy.
- CircCDYL encodes a truncated CDYL peptide (tCDYL-100) via N6-methylation, driving hypertrophy.
- tCDYL-100 disrupts the REST-CDYL-EHMT2 complex, activating rhoa and nppb transcription.
Conclusions:
- Uncovered a novel circRNA-derived peptide, tCDYL-100, in pathological cardiac hypertrophy.
- Revealed a regulatory mechanism involving N6-methyladenosine-circRNA-histone methylation.
- Demonstrated circCDYL's role in promoting cardiac hypertrophy through epigenetic modulation.
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.
