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Updated: Mar 14, 2026
Epigenetic Regulation of Cardiac Differentiation of Embryonic Stem Cells and Tissues
Published on: June 3, 2016
The chromatin-binding protein Smyd1 restricts adult mammalian heart growth
Sarah Franklin1, Todd Kimball2, Tara L Rasmussen3
1Department of Internal Medicine, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; and franklin@cvrti.utah.edu.
Insights
The histone methyltransferase Smyd1 restricts adult heart growth. Loss of Smyd1 causes cellular hypertrophy and heart failure, but its activation prevents pathological cell growth, offering new therapeutic targets for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Heart failure is characterized by cardiomyocyte hypertrophy, a condition linked to altered gene expression.
- Chromatin remodeling mechanisms controlling cell and organ size in the adult heart are not fully understood.
- Identifying novel regulators of cardiac growth is crucial for developing heart failure therapies.
Purpose of the Study:
- To identify muscle-specific chromatin regulators involved in cardiac hypertrophy and heart failure.
- To elucidate the role of the histone methyltransferase Smyd1 in regulating cardiomyocyte size and cardiac function.
- To explore Smyd1 as a potential therapeutic target for heart failure.
Main Methods:
- Quantitative proteomics was used to identify muscle-specific chromatin regulators in a mouse model of cardiac hypertrophy.
- Inducible loss-of-function studies in vivo were performed to assess the function of Smyd1 in the adult heart.
- Molecular studies were conducted to investigate Smyd1's role in gene expression regulation and its impact on cardiac pathology.
Main Results:
- Smyd1, a histone methyltransferase, was found to be upregulated in a mouse model of cardiac hypertrophy and heart failure.
- Loss of Smyd1 function led to cellular hypertrophy, cardiac remodeling, and severe heart failure in adult mice.
- Smyd1 acts as a muscle-specific regulator of gene expression, modulating isoforms linked to cardiac pathology.
- Activation of Smyd1 demonstrated a protective effect by preventing pathological cell growth.
Conclusions:
- Smyd1 is a critical regulator of cardiomyocyte size and plays a vital role in restricting organ growth in the adult heart.
- Dysregulation of Smyd1 contributes to cardiac hypertrophy and heart failure.
- Modulating Smyd1 activity presents a promising therapeutic strategy for treating cardiac hypertrophy and heart failure.
Abstract:
All terminally differentiated organs face two challenges, maintaining their cellular identity and restricting organ size. The molecular mechanisms responsible for these decisions are of critical importance to organismal development, and perturbations in their normal balance can lead to disease. A hallmark of heart failure, a condition affecting millions of people worldwide, is hypertrophic growth of cardiomyocytes. The various forms of heart failure in human and animal models share conserved transcriptome remodeling events that lead to expression of genes normally silenced in the healthy adult heart. However, the chromatin remodeling events that maintain cell and organ size are incompletely understood; insights into these mechanisms could provide new targets for heart failure therapy. Using a quantitative proteomics approach to identify muscle-specific chromatin regulators in a mouse model of hypertrophy and heart failure, we identified upregulation of the histone methyltransferase Smyd1 during disease. Inducible loss-of-function studies in vivo demonstrate that Smyd1 is responsible for restricting growth in the adult heart, with its absence leading to cellular hypertrophy, organ remodeling, and fulminate heart failure. Molecular studies reveal Smyd1 to be a muscle-specific regulator of gene expression and indicate that Smyd1 modulates expression of gene isoforms whose expression is associated with cardiac pathology. Importantly, activation of Smyd1 can prevent pathological cell growth. These findings have basic implications for our understanding of cardiac pathologies and open new avenues to the treatment of cardiac hypertrophy and failure by modulating Smyd1.
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