Four Dimensions of the Cardiac Myocyte Epigenome: from Fetal to Adult Heart

Abstract

Purpose of Review Development, physiological growth and the response of the heart to injury are accompanied by changes of the transcriptome and epigenome of cardiac myocytes. Recently, cell sorting and next generation sequencing techniques have been applied to determine cardiac myocyte-specific transcriptional and epigenetic mechanisms. This review provides a comprehensive overview of studies analysing the transcriptome and epigenome of cardiac myocytes in mouse and human hearts during development, physiological growth and disease. Recent Findings Adult cardiac myocytes express > 12,600 genes, and their expression levels correlate positively with active histone marks and inversely with gene body DNA methylation. DNA methylation accompanied the perinatal switch in sarcomere or metabolic isoform gene expression in cardiac myocytes, but remained rather stable in heart disease. DNA methylation and histone marks identified > 100,000 cis-regulatory regions in the cardiac myocyte epigenome with a dynamic spectrum of transcription factor binding sites. The ETS-related transcription factor ETV1 was identified as an atrial-specific element involved in the pathogenesis of atrial fibrillation. Summary Thus, dynamic development of the atrial vs. ventricular cardiac myocyte epigenome provides a basis to identify location and time-dependent mechanisms of epigenetic control to shape pathological gene expression during heart disease. Identifying the four dimensions of the cardiac myocyte epigenome, atrial vs. ventricular location, time during development and growth, and disease-specific signals, may ultimately lead to new treatment strategies for heart disease.

Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot

“…DNA methylation causes changes in the chromatin structure by covalent modification of DNA and histones, causes repression of fetal heart genes, and activates the expression of sarcomeric components of mature CMCs. In the perinatal period, methylation and expression of about 440 CMCs genes are known to change [ 127 , 128 ]. Thus, during this period, the fetal troponin I1 isoform (Tnni1) is repressed by methylation, and, on the contrary, the postnatal Troponin I3 isoform (Tnni3) is activated through demethylation [ 127 , 129 ].…”

Environmental Alterations during Embryonic Development: Studying the Impact of Stressors on Pluripotent Stem Cell-Derived Cardiomyocytes

“…DNA methylation and histone modifications are highly dynamic in shaping the cardiomyocytes transcriptome during development and postnatal maturation [99]. The dynamic epigenetic status during the differentiation from progenitor cells to CMs has been investigated [100]; however, the detailed epigenetic process leading to cardiac alterations during embryonic development has been only recently investigated and not fully uncovered yet [99,101,102].…”

“…During cardiac development, DNA methylation and transcriptional changes have been identified for around 440 cardiac genes [99,101,103]. Of interest, methylation patterns of CMs exposed to pathological stress partially resemble those of foetal CMs, suggesting how the adaptation is firmly linked to changes in gene regulation and activity [97].…”

Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology

“…During this time, there starts to be a profound switch in cardiac metabolism, where the heart goes from primarily consuming glucose to fatty-acids [ 18 ]. Associated with this metabolic switch are changes in the cardiac epigenome and cardiac excitation-contraction coupling [ 19 ]. As the heart develops, both the myocyte action potential amplitude and duration increase [ 20 ].…”