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Epigenetics of Aberrant Cardiac Wound Healing

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Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451‐491, 2018.

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Figure 1. Figure 1. Schematic overview highlighting epigenetic changes associated with cardiac injury that lead to the acquisition of hyperactive cellular phenotypes in cardiomyocytes, fibroblasts and immune cells, and promote aberrant pathological remodeling in the heart.
Figure 2. Figure 2. Regulation of gene transcription by DNA methylation and demethylation in the promoter region. The addition of a methyl group (‐CH3) to carbon 5 on the cytosine ring (C), is catalysed by the DNA methyltransferase (DNMT) enzymes forming 5‐methylcytosine (5MeC). S‐adenosylmethionine (SAM) is utilized as a methyl donor that is subsequently converted to S‐adenosylhomocysteine (SAH) upon donation. Methyl‐CpG‐binding proteins (MeCP) and methyl‐CpG‐binding domain protein (MBD) proteins are recruited to 5MeC resulting in gene silencing by preventing transcription factor (TF) and binding of RNA polymerase II (RNApolII) binding. Conversely, removal of methylated cytosines can be enzymatically carried out by the ten‐eleven translocation (TET) enzymes, which oxidize 5MeC to 5‐hydroxymethylcytosine (5hMeC). Small molecule inhibitors of DNMT activity prevent 5MeC formation and together these processes promote gene expression by allowing TF and RNApolII to bind to the DNA.
Figure 3. Figure 3. Control of gene expression through regulation of chromatin structure by acetylation and methylation of histone proteins. Formation of heterochromatin structure and repression of gene expression is facilitated by both the removal of acetyl groups from histone tails by histone deacetylases (HDACs) and the actions of histone lysine methyltransferases (HMTs) and demethylases (HDMs) forming repressive histone marks (H3K9, H3K20, H3K27). Conversely, promotion of gene expression and euchromatin structure is carried out by enzymatic addition of acetyl groups by histone acetyltransferases (HATs) and the actions of HMTs and HDMs forming active histone marks (H3K4, H3K26, H3K79). Abbreviations: HMTs, histone methyltransferases; HDMs, histone demethylases; HATs, histone acetyltransferases; HDACs, histone deacetylases; CH3, methyl group. Yellow pentagon: active histone marks, blue pentagon: repressive histone marks, green marks: active acetylation marks.

Figure 1. Schematic overview highlighting epigenetic changes associated with cardiac injury that lead to the acquisition of hyperactive cellular phenotypes in cardiomyocytes, fibroblasts and immune cells, and promote aberrant pathological remodeling in the heart.

Figure 2. Regulation of gene transcription by DNA methylation and demethylation in the promoter region. The addition of a methyl group (‐CH3) to carbon 5 on the cytosine ring (C), is catalysed by the DNA methyltransferase (DNMT) enzymes forming 5‐methylcytosine (5MeC). S‐adenosylmethionine (SAM) is utilized as a methyl donor that is subsequently converted to S‐adenosylhomocysteine (SAH) upon donation. Methyl‐CpG‐binding proteins (MeCP) and methyl‐CpG‐binding domain protein (MBD) proteins are recruited to 5MeC resulting in gene silencing by preventing transcription factor (TF) and binding of RNA polymerase II (RNApolII) binding. Conversely, removal of methylated cytosines can be enzymatically carried out by the ten‐eleven translocation (TET) enzymes, which oxidize 5MeC to 5‐hydroxymethylcytosine (5hMeC). Small molecule inhibitors of DNMT activity prevent 5MeC formation and together these processes promote gene expression by allowing TF and RNApolII to bind to the DNA.

Figure 3. Control of gene expression through regulation of chromatin structure by acetylation and methylation of histone proteins. Formation of heterochromatin structure and repression of gene expression is facilitated by both the removal of acetyl groups from histone tails by histone deacetylases (HDACs) and the actions of histone lysine methyltransferases (HMTs) and demethylases (HDMs) forming repressive histone marks (H3K9, H3K20, H3K27). Conversely, promotion of gene expression and euchromatin structure is carried out by enzymatic addition of acetyl groups by histone acetyltransferases (HATs) and the actions of HMTs and HDMs forming active histone marks (H3K4, H3K26, H3K79). Abbreviations: HMTs, histone methyltransferases; HDMs, histone demethylases; HATs, histone acetyltransferases; HDACs, histone deacetylases; CH3, methyl group. Yellow pentagon: active histone marks, blue pentagon: repressive histone marks, green marks: active acetylation marks.
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Teaching Material

A. Russell-Hallinan, C. J. Watson, J. A. Baugh. Epigenetics of Aberrant Cardiac Wound Healing. Compr Physiol. 8: 2018, 451-491.

Didactic Synopsis

Cardiac remodeling is a crucial feature of myocardial responses to injury. Epigenetic alterations and regulation of this multifactorial process are at the forefront of cardiac remodeling research, including the delineating of cell-type specific contributions. This comprehensive review will support undergraduate and postgraduate teaching of concepts relating to the role of epigenetics in dictating inflammatory, fibrotic, and hypertrophic responses in the context of cardiac injury.

Major Teaching Points:

  1. Understanding wound healing responses of both resident cardiac cells and infiltrating inflammatory cells, in pathological settings such as myocardial infarction and pressure overload, is necessary to appreciate the complex pathophysiology that leads to the development of heart failure.
  2. Epigenetic mechanisms such as DNA methylation and posttranslational modifications (acetylation and methylation) of histone tails are important regulators of gene expression and are now considered to be involved in promoting abnormal cardiac wound healing through, extracellular matrix deposition, myocyte hypertrophy, and inflammatory mediator release.
  3. Epigenetic mechanisms critically regulate cellular phenotype and function:
    1. Alterations in DNA methylation (e.g., DNMT3 enzymes) and histone modifications (e.g., HDAC2) can influence the hypertrophic response in postmitotic cardiomyocytes.
    2. Increased DNA methylation in cardiac fibroblasts is associated with sustained activation and extracellular matrix deposition.
    3. Immune cell phenotype, cytokine release, and immune response (trained immunity vs. immunotolerance) are regulated by both DNA methylation and histone modifications.
  4. Advancements in therapeutic targeting or manipulation of the epigenetic machinery in cells implicated in aberrant cardiac remodeling may yield novel treatment strategies in the future management of cardiac diseases including heart failure.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: This illustrated figure demonstrates that various types of injury to the heart can drive epigenetic changes in cardiomyocytes, fibroblasts, and immune cells. These epigenetic changes can result in the acquisition of aberrant phenotypes which drive pathological remodeling in the heart which ultimately leads to the development of heart failure.

Figure 2. Teaching points: This illustrated figure highlights the regulation of gene expression by DNA methylation (gene repression) and demethylation (gene activation) at the promoter region of a gene.

Figure 3. Teaching points: This illustrated figure facilitates understanding of gene regulation by modifications of the amino-terminal tails of histone proteins, focusing on specifically the modifications acetylation and methylation. It also highlights the active and repressive histone marks that are associated with active gene expression or gene silencing.

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How to Cite

Adam Russell‐Hallinan, Chris J. Watson, John A. Baugh. Epigenetics of Aberrant Cardiac Wound Healing. Compr Physiol 2018, 8: 451-491. doi: 10.1002/cphy.c170029