Epigenetic mechanisms in heart development and disease

Abstract

Suboptimal intrauterine development has been linked to predisposition to cardiovascular disease in adulthood, a concept termed 'developmental origins of health and disease'. Although the exact mechanisms underlying this developmental programming are unknown, a growing body of evidence supports the involvement of epigenetic regulation. Epigenetic mechanisms such as DNA methylation, histone modifications and micro-RNA confer added levels of gene regulation without altering DNA sequences. These modifications are relatively stable signals, offering possible insight into the mechanisms underlying developmental origins of health and disease. This review will discuss the role of epigenetic mechanisms in heart development as well as aberrant epigenetic regulation contributing to cardiovascular disease. Additionally, we will address recent advances targeting epigenetic mechanisms as potential therapeutic approaches to cardiovascular disease.

Figure 1. The roles of major epigenetic mechanisms in key stages of heart development

Cardiac progenitors derived from lateral plate mesoderm migrate to the cardiogenic region to form the cardiac crescent and later the primitive heart tube. Cardiac looping ensures proper orientation of the future atria, ventricles and outflow tract. Finally, development of the conduction and valvular systems, as well as septation of atria, ventricles and outflow tract, results in the four-chambered heart. Cardiomyocyte terminal differentiation, which occurs well after the formation of the four-chambered heart, determines final cardiac contractile endowment. Epigenetic regulatory mechanisms have been described in all stages of heart development. miRs have been shown to regulate cellular differentiation processes in early heart development (miR-1 and miR-499) as well as cardiomyocyte proliferation and terminal differentiation (miR-133). Histone modifications regulate right ventricle development (SMYD1) as well as cardiac septation (Jumonji and LSD-1) and cardiomyocyte function and proliferation (HDACs 1–3). DNA methylation also contributes to outflow tract septation[s14] and cardiomyocyte proliferation and terminal differentiation. Abbreviations: HMT, histone methyltransferases; DNAme, DNA methylation; HDM, histone demethylases; HDAC, histone deacetylases; LSD-1, lysine-specific demethylase; miR, micro-RNA.

Figure 2. Epigenetic mechanisms in cardiovascular diseases contributing to heart failure

Regardless of anatomical location, epigenetic mechanisms are emerging as crucial orchestrators of cardiovascular diseases, including previously idiopathic diseases such as essential hypertension or certain cardiomyopathies. (a) Epigenetic mechanisms associated with hypertension and arrhythmias. Differential DNA methylation or expression of miRs detectable in the peripheral blood of patients suffering from left ventricular afterload or conduction disorders can aid in the early detection and diagnosis of disease. In addition, identifying epigenetic mechanisms that contribute to hypertension or arrhythmias (such as methylation of histone H3 or miR-328) or have protective effects (miR-133, miR-1, miR-208a) could aid in the development of therapies for these diseases. (b) Epigenetic mechanisms associated with coronary artery disease and cardiomyopathies. Epigenetic mechanisms can have prognostic value (such as methylation of LINE repetitive elements) or potentially protective effects (H3 acetylation/methylation or H4 acetylation) in coronary artery disease. In addition, DNA methylation and miR expression can serve as diagnostic and prognostic tools for cardiomyopathies.

Figure 2. Epigenetic mechanisms in cardiovascular diseases contributing to heart failure

Regardless of anatomical location, epigenetic mechanisms are emerging as crucial orchestrators of cardiovascular diseases, including previously idiopathic diseases such as essential hypertension or certain cardiomyopathies. (a) Epigenetic mechanisms associated with hypertension and arrhythmias. Differential DNA methylation or expression of miRs detectable in the peripheral blood of patients suffering from left ventricular afterload or conduction disorders can aid in the early detection and diagnosis of disease. In addition, identifying epigenetic mechanisms that contribute to hypertension or arrhythmias (such as methylation of histone H3 or miR-328) or have protective effects (miR-133, miR-1, miR-208a) could aid in the development of therapies for these diseases. (b) Epigenetic mechanisms associated with coronary artery disease and cardiomyopathies. Epigenetic mechanisms can have prognostic value (such as methylation of LINE repetitive elements) or potentially protective effects (H3 acetylation/methylation or H4 acetylation) in coronary artery disease. In addition, DNA methylation and miR expression can serve as diagnostic and prognostic tools for cardiomyopathies.