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.
Highlights
Congenital heart disease (CHD) is characterized by improper heart formation manifesting as defects involving the heart walls, valves, or blood vessels
Several lineage-tracing experiments have demonstrated that the first heart field (FHF) gives rise to the left ventricle (LV) and parts of the left atrium, while the second heart field (SHF) populates the entire right heart, parts of the left atrium, the majority of the outflow tracts (OFTs), and the proepicardium (Figure 1f) [25,27,28]
Decades of research have found that SMyD1 can control gene expression by (1) repressing transcriptional activity via association with HDAC1-3 and NCoR/SMRT complexes [85], (2) activating transcriptional activity by catalyzing H3K4me3 [86], (3) localizing to muscle-specific promotors via association with the transcription factor skNAC1 [85], or (4) catalyzing post-translational modifications on ER stress proteins, which are necessary for cardiomyocyte proliferation and survival [87]
Summary
Congenital heart disease (CHD) is characterized by improper heart formation manifesting as defects involving the heart walls, valves, or blood vessels. Heart development is controlled by several overlapping morphogenic systems that regulate intricate cardiac transcriptional networks. Single mutations in specific morphogens, their target transcription factors, or downstream cardiac genes have been shown to be independently sufficient to cause ~10% of CHD; for the majority of cases, the cause remains unknown [10,11,12,13,14,15,16,17,18]. To advance the diagnosis, understanding, and treatment of CHD, the extra-genomic factors critical for heart development need to be uncovered. Research in mechanobiology has identified a number of mechanosensitive pathways that regulate cardiac development, and epigenetic modifiers have been implicated as key regulatory components of flow-responsive signaling pathways. This review aims to summarize the current understanding of heart development and the extra-genomic systems that, when perturbed, can cause CHD
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