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.

Keywords: DNA methylation; biomarkers; cardiac development; congenital heart defects; endocardium; hemodynamics; histone modification; maternal diabetes; mechanotransduction; microRNA.

Figure 1

Human heart development. (a) The implanted blastocyst quickly forms the bilaminar embryo. The primitive streak forms in the epiblast, and an epithelial-to-mesenchymal transition (EMT) near the streak causes gastrulation to begin. (b) Bilateral migration of the first heart field (FHF) and second heart field (SHF) yields the cardiac crescent and endocardial tubes. (c) The bilateral cardiogenic regions fuse to form the bilaminar linear heart tube. SHF cells migrate into the poles, and the primitive outflow tract (OFT) begins to fuse with the dorsal aorta. (d) Asymmetry is broken with leftward cardiac looping. The proepicardium undergoes EMT to form the epicardium. Inset: trabeculation, compaction, and formation of the primitive coronary vasculature. (e) Neural crest cells migrate to populate the OFTs. Insets: Septa separate the truncus arteriosus and the left and right heart; the endocardial cushions give rise to the four valves. (f) The postnatal human heart.

Figure 2

Mechanisms of Epigenetic Modification. Representative histone marks are depicted, but there are several other sites of histone methylation and acetylation. By altering chromatin structure, H3K27me3 and H3K9me3 inhibit transcription, while H4K5ac, H3K9ac, H3K3me3, and H3K4me3 promote transcription. Figure inspired by [67,68]. Reproduced with permission from D’Addario, et al., FEBS Journal; John Wiley and Sons, 2013 and Joosten, et al., Nature Reviews Urology; Springer Nature, 2018.

Figure 3

Mechanosensitive pathways involved in heart development. During chamber morphogenesis, hemodynamic forces control endocardial cell proliferation and, through Klf2a, direct endocardial cell morphology. Blood flow also has an impact on myocardial wall integrity, an effect that is mediated by klf2 expression in the endocardium. Cilia sense fluid forces and activate Notch1 signaling to regulate trabeculation. During valve development, Klf2a responds to blood flow to activate Bmp4 in the myocardium and fibronectin synthesis in the extracellular matrix (ECM). Klf2a is positively regulated by mechanosensitive ion channels Trpv4 and Trpp2 and suppressed by cerebral cavernous malformation (CCM) proteins and the chromatin modifier Hdac5. Stretch induces endocardial endothelin converting enzyme 1 (ECE1) and myocardial Cx40 expression, which controls Purkinje fiber differentiation. Flow-responsive miR-21 regulates proliferation in the developing valves. Hyaluronan synthase 2 (Has2) produces hyaluronic acid, an important component of the ECM. Shear stress-responsive miR-23 regulates Has2 and is critical for valve formation. miR-143 inhibits retinoic acid (RA) signaling in a spatially-controlled manner during cardiogenesis.

Figure 4

The disruption of highly synchronized regulators of gene expression leads to congenital heart disease. Crosstalk between genetics, mechanics, epigenetics, CHD, and the environment.