AdvancedMedical students

Epigenetics in Dilated Cardiomyopathy – a medical student article

Abstract: Dilated cardiomyopathy (DCM) is the most diagnosed and the one with the highest morbidity among all of the cardiomyopathies. Although it is studied that gene mutations are the main reason for the disease in this review we will pay attention to the epigenetics in DCM and mainly the Deoxyribonucleic acid (DNA) methylation mechanism and the results from some of the studies about how methylation affects the development of DCM.

Key words: dilated cardiomyopathy, genes, epigenetics

Introduction:

  Cardiomyopathies are heart diseases that affect the heart muscle and are not the result of hypertension, coronary arterial, ischemic, valvular or pericardial abnormalities. These diseases are classified mainly into three morphologic types (dilated, restrictive and hypertrophic) on the basis of their pathophysiology and clinical presentation.[1] Dilated cardiomyopathy (DCM) is defined as a myocardial disorder, characterized by an enlarged and poorly contractile LV, leading to systolic disfunction. The etiology of DCM often has a genetic background. Numerous genes and alleles including the ones encoding cytoskeletal and mitochondrial proteins, sarcomere components and desmosomal structures are attributed to DCM, making genetic testing one of the most important parts in diagnosing and prevention the disease. In the last years attention is placed on epigenetics, which are mostly focusing on the regulatory mechanisms and the functional consequences in gene expression rather in gene sequences. [2,3]

Epigenetics in DCM:

  There are four major epigenetic modifications connected with DCM – Deoxyribonucleic acid (DNA) methylation, histone modification, chromatin remodeling and noncoding ribonucleic acids (RNAs). This article will pay attention to the DNA methylation process, the one mostly implicated in DCM. Adding a methyl (CH3) group at 5′-C-phosphate-G-3′ (CpG) site in DNA is one of the most widespread covalent modification to DNA in human genome, which is carried out by a family of DNA methyltransferases, including DNA (cytosine-5)-methyltransferase 1 (DNMT1), 3A, and 3B.[3] DNA methylation is associated with gene repression or activation, depending on the site of the methylation process in DNA. The dynamic changes of DNA methylation are crucial for cell differentiation during normal development and diseases, including cardiomyocyte lineage determination, maturation, making DNA methylation important mechanism of epigenetic regulation.[3]

DNA methylation and DCM studies:

  The first genome-wide maps of DNA methylation from normal human hearts and end-stage cardiomyopathic hearts, was firstly reported from Movassagh et al and it was created using DNA captured by immunoprecipitation with anti-methylated cytosine antibody. The study showed for the first time that in cardiomyopathy, DNA methylation in CpG islands was globally altered. The same results were shown by a separate study by Haas et al. The role of DNA methylation in cardiac gene regulation and the development of DCM is supported by both of these studies.
According to Meder et al. in which study left-ventricular biopsies and whole peripheral blood samples from 135 DCM patients were used, the DNA methylation patterns again showed significant association with DCM. The interesting result from this study is that they found specific epigenetic methylation patterns that are conserved between cardiac and peripheral blood, demonstrating the potential of using these patterns as epigenetic biomarkers for DCM diagnosis. [3]

Haas et al. performed two-staged, funnel-like DNA methylation mapping in Idiopathic DCM patients and controls. Using the Infinium Human Methylation 27 platform they assessed genome DNA methylation levels of CpG islands. They found that 12 out of 20 genes showed the same direction of dys-methylation as found in the screening stage and four reached statistical significance, which means that the dys-methylated and dys-regulated genes also have a functional role in the heart. [4]

Conclusion:

  In the last years, it has been recognized that not only genetic mutations, but also epigenetic dysregulations play a vital role during the development of DCM. [3] In this review we discussed one major form of epigenetic modulation – DNA methylation and its place in DCM. The constantly increasing complexity of the epigenetic regulatory network gives us exciting opportunities to better understand the principles underlying the development of DCM, presents both challenges, as well as a clear path for future diagnostic and therapeutic strategies for DCM. [3]

Author
Strahil Vasilev – Medical University, Sofia

Sources

[1] Loscalzo, J. (c2010). Harrison’s Cardiovascular Medicine. (17th ed.). : .

[2] Elizabeth, M & Mestroni, L. (2017). Dilated cardiomyopathy: genetic
determinants and mechanisms. Circulation Research , 121(7), 731-748.

Link to the full article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626020/

[3] – Yu, J, Zeng, C & Wang, Y. (2019). Epigenetics in dilated cardiomyopathy. Curr Opin
Cardiol, 34(3), 260–269.

Link to the full article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581652/

[4] – Haas et al.. (2013). Alterations in cardiac DNA methylation in human dilated
cardiomyopathy. EMBO Molecular Medicine, 5(3), 413-429.

Link to the full article: https://www.embopress.org/doi/10.1002/emmm.201201553

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