The chromatin-binding protein Smyd1 restricts adult mammalian heart growth

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.

Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart

“…Recently, we found that Smyd1 expression is differentially regulated during pressure overload cardiac hypertrophy and failure in mice (4), consistent with its expression in the failing human heart (5). In addition, we showed that loss of Smyd1 in the adult mouse heart was sufficient to induce hypertrophic growth, which progressed to fulminant heart failure (4). Analysis of the cardiac transcriptome in these Smyd1-KO mice revealed dysregulation of pathways responsible for development, muscle growth, and metabolism (4).…”

“…Our initial analysis of inducible, cardiac-specific Smyd1-KO revealed down-regulation of numerous genes involved in metabolism. However, these transcriptomic changes were accompanied by significant structural remodeling of the heart and severe heart failure (4). Thus, Significance Smyd1 is a muscle-specific histone methyltransferase, and its role in the regulation of growth and differentiation in skeletal and cardiac muscle is well established.…”

“…In addition, we showed that loss of Smyd1 in the adult mouse heart was sufficient to induce hypertrophic growth, which progressed to fulminant heart failure (4). Analysis of the cardiac transcriptome in these Smyd1-KO mice revealed dysregulation of pathways responsible for development, muscle growth, and metabolism (4). However, it remained unclear whether metabolic remodeling in Smyd1-KO mice is purely a consequence of hypertrophic cell growth or is an independent factor in the progression toward heart failure in this model.…”

“…It was identified initially as an essential regulator of cardiac differentiation and morphogenesis in systemic Smyd1-knockout (Smyd1-KO) mice, which die in utero due to cardiac defects (3). Recently, we found that Smyd1 expression is differentially regulated during pressure overload cardiac hypertrophy and failure in mice (4), consistent with its expression in the failing human heart (5). In addition, we showed that loss of Smyd1 in the adult mouse heart was sufficient to induce hypertrophic growth, which progressed to fulminant heart failure (4).…”

The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system

“…Further, ROS decreased levels of the H3K4 methyltransferase SET and MYND domain‐containing protein 1 (SMYD1) in a model of cardiac pressure overload, and thioredoxin restored SMYD1 levels (Figure ) and cardiac function indicating that HMTs might differ in their ROS sensitivity depending on the pathophysiological context although histone lysine methylation was not determined in this study (Liu et al , ). As activation of SMYD1 has been considered to prevent cardiac hypertrophy and even heart failure, such a ROS‐related pathway might have important implications for further cardiovascular therapies (Franklin et al , ).…”