Cardiac development is a precisely regulated process governed by both genetic and epigenetic mechanisms. Among these, DNA methylation is one mode of epigenetic regulation that plays a crucial role in controlling gene expression at various stages of heart development and maturation. Understanding stage-specific DNA methylation dynamics is critical for unraveling the molecular processes underlying heart development from specification of early progenitors, formation of a primitive and growing heart tube from heart fields, heart morphogenesis, organ function, and response to developmental and physiological signals. This review highlights research that has explored profiles of DNA methylation that are highly dynamic during cardiac development and maturation, exploring stage-specific roles and the key molecular players involved. By exploring recent insights into the changing methylation landscape, we aim to highlight the complex interplay between DNA methylation and stage-specific cardiac gene expression, differentiation, and maturation.
Keywords: Heart development; cardiac progenitors; cardiogenesis; cell differentiation; epigenetics; epigenomics; pluripotent stem cells.
In general, different cell types all contain the same DNA which includes about 30,000 genes embedded in chromosomes. During development starting from a fertilized egg, cells take on specific identities associated with a specific organ system based on turning some genes on, while turning other genes off. Since the genes themselves do not change, the process by which cells inherit and remember their identity is referred to as epigenetics. What does change are modifications of proteins, particularly those of histones that package DNA in the chromosomes, as well as DNA methylation. Methylation places a methyl chemical group onto a cytosine residue to form 5-methyl-C, which is often considered a fifth type of DNA nucleotide. In this review, we describe the protein enzymes that place methyl groups onto DNA and those that work to remove such marks, all of which have a tremendous impact on whether genes are turned on or off. Recently there has been much interest in understanding how these “epigenomic” marks direct expression of genes to commit cells into specific fates, including those cells that make up a developing heart. Research is described exploring DNA methylation patterns in the developing heart using mouse models, human tissues, and stem cells that are directed to differentiate into heart tissue. The patterns of methylation are very dynamic, and this appears to be very important for turning the appropriate genes on or off as cells progressively move through different stages of heart cell development and maturation. Mutations in the regulatory genes that control methylation cause major defects in heart formation. Current research seeks to understand how the methylation machinery is targeted to specific gene regulatory sequences at the right time and place to help coordinate heart formation.