Epigenetics and Mechanobiology in Heart Development and Congenital Heart Disease

Abstract

: Congenital heart disease (CHD) is the most common birth defect worldwide and the number one killer of live-born infants in the United States. Heart development occurs early in embryogenesis and involves complex interactions between multiple cell populations, limiting the understanding and consequent treatment of CHD. Furthermore, genome sequencing has largely failed to predict or yield therapeutics for CHD. In addition to the underlying genome, epigenetics and mechanobiology both drive heart development. A growing body of evidence implicates the aberrant regulation of these two extra-genomic systems in the pathogenesis of CHD. In this review, we describe the stages of human heart development and the heart defects known to manifest at each stage. Next, we discuss the distinct and overlapping roles of epigenetics and mechanobiology in normal development and in the pathogenesis of CHD. Finally, we highlight recent advances in the identification of novel epigenetic biomarkers and environmental risk factors that may be useful for improved diagnosis and further elucidation of CHD etiology.

Exploring the Role of Maternal Nutritional Epigenetics in Congenital Heart Disease

“…The phenotypic differences found despite the identical genotype are attributed to epigenetic regulation. Epigenetics is an extra-genomic gene regulator ( 19 ) and epigenotype is mitotically inheritable and is a potentially reversible molecular alteration of the DNA sequence and chromatin ( 20 ). This inheritance plays an important role in maintaining stable gene expression in differentiated cells defining their identity ( 21 ).…”

“…Polygenic diseases such as CHD have been proven to have altered epigenetic patterns through the experimental and clinical research until today ( 19 ). The epigenetic set of modifications is diverse in nature and the epigenetic mechanisms include DNA methylation, noncoding RNA (ncRNA)–mediated gene regulation, and histone modifications with consequent chromatin remodeling.…”

“…Stages of development of the human heart and heart defects arising at each stage were well summarized in a recent review ( 19 ). Pathogenic cardiac remodeling that raises the chances of defects during heart development is also attributed to epigenetic alterations and mechanobiological events ( 19 ).…”

“…Stages of development of the human heart and heart defects arising at each stage were well summarized in a recent review ( 19 ). Pathogenic cardiac remodeling that raises the chances of defects during heart development is also attributed to epigenetic alterations and mechanobiological events ( 19 ). Diversified gene expression profiles in different cells and tissues or maintaining the state of tissue differentiation are facilitated by epigenetic mechanisms ( 22 ).…”

Engineering Myocardium for Heart Regeneration—Advancements, Considerations, and Future Directions

“…The muscular heart walls are composed of a thick myocardial layer sandwiched between two single-cell layers called the endocardium (blood-contacting surface) and the epicardium (outer layer of heart). Both the epicardium and endocardium are essential for proper myocardial development, growth, and remodeling (7,8). In the ventricular myocardium, overlaying layers of cardiomyocytes are oriented in left-handed, circumferential, or right-handed directions, resulting in an efficient torsional "wringing" motion of contraction (9,10).…”