Abstract
Histone acetylation has been linked to cardiac hypertrophy and heart failure. However, the pathological implications of changes in histone methylation and the effects of interventions with histone methyltransferase inhibitors for heart failure have not been fully clarified. Here, we focused on H3K9me3 status in the heart and investigated the effects of the histone H3K9 methyltransferase inhibitor chaetocin on prognoses in Dahl salt-sensitive rats, an animal model of chronic heart failure. Chaetocin prolonged survival and restored mitochondrial dysfunction. ChIP-seq analysis demonstrated that chronic stress to the heart induced H3K9me3 elevation in thousands of repetitive elements, including intronic regions of mitochondria-related genes, such as the gene encoding peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Furthermore, chaetocin reversed this effect on these repetitive loci. These data suggested that excessive heterochromatinization of repetitive elements of mitochondrial genes in the failing heart may lead to the silencing of genes and impair heart function. Thus, chaetocin may be a potential therapeutic agent for chronic heart failure.
Highlights
Transcription factor access to the DNA and the recruitment of transcriptional complexes to gene promoter/ enhancer regions[15]
The expression of the gene encoding natriuretic peptide precursor A (Nppa), a marker of heart failure, was upregulated in left ventricular (LV) tissues in the HF group, and this increase in expression was significantly suppressed by chaetocin administration (Fig. 1C)
We demonstrated that the histone H3K9 methyltransferase inhibitor chaetocin blocked the progression of heart failure and alleviated mitochondrial dysfunction
Summary
Transcription factor access to the DNA and the recruitment of transcriptional complexes to gene promoter/ enhancer regions[15]. Histone acetylation and deacetylation are known to play a role in the development of cardiac hypertrophy and heart failure[16,17]. Additional evidence suggests that histone methylation on lysine 4 (K4), K9, or K36 of histone H3 are involved in cardiac remodeling[30,31,32,33] Both histone methylation and histone acetylation may act as therapeutic targets for the management of heart failure. Neither the role of H3K9me[3] on repetitive loci in the failing heart nor the efficacy of histone methyltransferase inhibitors in heart failure has been clarified. In this study, we investigated H3K9 trimethylation status on repetitive elements in the failing heart and hypothesized that the histone-modifying enzyme affecting H3K9 trimethylation status may play an important role in heart failure. We showed that chaetocin delayed the transition from hypertrophy to heart failure, restored mitochondrial dysfunction in failing hearts, and prolonged animal survival
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
