Congenital heart disease (CHD) is the most prevalent birth defect worldwide. Many forms of congenital heart disease, including left ventricular non-compaction cardiomyopathy (LVNC) and hypoplastic left heart syndrome (HLHS), are associated with defective cardiac myogenesis, which further compromises cardiac contractile function (Zhang, Chen, Qu, Chang, & Shou, 2013).

To study the pathogenesis of CHD, the most popular in vivo model system is mice. Lineage tracing studies in mice have revealed that there are two sources of cardiac progenitors: first heart field progenitors and second heart field progenitors. These progenitors are defined by a different embryonic region and give rise to cardiomyocytes (Buckingham, Meilhac, & Zaffran, 2005). Early ventricular cardiomyocytes derived from the first heart field progenitors that primarily contribute to the left ventricle, are specified at an earlier stage of heart development. In contrast, cardiac progenitors from the second heart field give rise to cardiomyocytes that mainly constitute myocardium in the atria, outflow tract, and right ventricle (Buckingham et al., 2005). Myocardial wall growth/expansion consists of two separate, but closely associated processes: trabeculation and compaction. In mice, trabeculation initiates at embryonic day (E) 8.5, when cardiomyocytes protrude into the ventricular lumen and form trabecular ridges (Li et al., 2016; Passer, van de Vrugt, Atmanli, & Domian, 2016). The trabeculae are surrounded by a layer of endothelial cells (i.e., endocardium) with cardiac jelly separating the trabeculae and endocardium. The trabeculae extend radially to form a trabecular network and terminate at E14.5, part of which later become a part of the ventricular compact layer (Sedmera, Pexieder, Vuillemin, Thompson, & Anderson, 2000). In addition to intrinsic signals within trabecular myocardium, signaling crosstalk between endocardium and myocardium (e.g., Notch signaling) instructs dynamic trabecular development (Del Monte-Nieto et al., 2018). Similarly, compact myocardial growth is supported by growth cues from the epicardium (Quijada, Trembley, & Small, 2020).

These myocardial growth events require finely tuned epigenetic regulation to regulate gene expression and cellular function during heart development. Chromatin compacts the genome, and epigenetic modifications regulate chromatin accessibility of transcription factors. Cardiac development is tightly associated with epigenetic programs that regulate gene expression under the control of tissue specific transcriptional programs (Akerberg & Pu, 2020). Although genetic mutations play important roles in the etiology of CHD, it is not uncommon that no inherited and de novo mutations are identified in CHD probands, implying some other factors such as epigenetics may also contribute to the disease mechanisms. Thus, further understanding of epigenetic regulation of myocardial development likely provides further insights into the CHD pathogenesis (Zaidi et al., 2013). Along with others, our recent research findings suggest that epigenetics in non-myocardial compartments also play critical roles in driving myocardial development (Jang et al., 2022; Jang et al., 2023). This review will focus on selected epigenetic regulatory factors that orchestrate myocardial growth.