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Histone H4K20 Trimethylation Is Decreased in Murine Models of Heart Disease
Samuel M Hickenlooper1, Kathryn Davis1, Marta W Szulik1
1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112, United States.
Insights
Histone H4K20 trimethylation, a key epigenetic mark, is newly studied in heart disease. Its levels change with cardiac stress, offering insights into heart dysfunction and potential therapeutic targets.
Area of Science:
- Epigenetics
- Cardiovascular Science
- Molecular Biology
Background:
- Heart disease is a leading cause of death globally.
- Cardiac dysfunction involves transcriptomic and epigenetic alterations.
- Histone modifications, like methylation, regulate gene expression in the heart.
Purpose of the Study:
- To investigate histone H4K20 trimethylation in cardiac dysfunction.
- To determine the role of H4K20 methylation in heart disease.
- To identify enzymes regulating H4K20 methylation in heart failure.
Main Methods:
- Immunoblotting and mass spectrometry to quantify H4K20 trimethylation.
- Analysis of cell and animal models of cardiac dysfunction.
- Examination of public datasets for enzyme expression in heart failure patients.
Main Results:
- Histone H4K20 trimethylation is differentially regulated in cardiomyocytes.
- Increased H4K20 trimethylation observed during acute hypertrophic stress.
- Decreased H4K20 trimethylation noted in sustained ischemic injury and cardiac dysfunction.
Conclusions:
- This is the first study to examine H4K20 trimethylation in the heart.
- H4K20 trimethylation is dynamically regulated in response to cardiac stress.
- Specific enzymes regulating H4K20 methylation are differentially expressed in heart failure.
Abstract:
Heart disease is the leading cause of death in the developed world, and its comorbidities such as hypertension, diabetes, and heart failure are accompanied by major transcriptomic changes in the heart. During cardiac dysfunction, which leads to heart failure, there are global epigenetic alterations to chromatin that occur concomitantly with morphological changes in the heart in response to acute and chronic stress. These epigenetic alterations include the reversible methylation of lysine residues on histone proteins. Lysine methylations on histones H3K4 and H3K9 were among the first methylated lysine residues identified and have been linked to gene activation and silencing, respectively. However, much less is known regarding other methylated histone residues, including histone H4K20. Trimethylation of histone H4K20 has been shown to repress gene expression; however, this modification has never been examined in the heart. Here, we utilized immunoblotting and mass spectrometry to quantify histone H4K20 trimethylation in three models of cardiac dysfunction. Our results show that lysine methylation at this site is differentially regulated in the cardiomyocyte, leading to increased H4K20 trimethylation during acute hypertrophic stress in cell models and decreased H4K20 trimethylation during sustained ischemic injury and cardiac dysfunction in animal models. In addition, we examined publicly available data sets to analyze enzymes that regulate H4K20 methylation and identified two demethylases (KDM7B and KDM7C) and two methyltransferases (KMT5A and SMYD5) that were all differentially expressed in heart failure patients. This is the first study to examine histone H4K20 trimethylation in the heart and to determine how this post-translational modification is differentially regulated in multiple models of cardiac disease.
