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The role of epigenetics in the origin of congenital heart disease

Rik De Decker, MSc, MB ChB, DCH, FCPaeds (SA), Cert Med Genetics (Paeds)

Senior specialist paediatric cardiologist, Division of Critical Care and Children’s Heart Diseases, Red Cross War Memorial Children’s Hospital, Cape Town

Correspondence to: Rik De Decker (rik.dedecker@uct.ac.za)

The past decade has seen a remarkable explosion of insights into the control of heart development. This has come about as a consequence of the temporal confluence of several research domains: the better delineation of syndromic congenital heart disease (see article in this issue), the completion of the Human Genome Project in 2003, the remarkable advances in molecular embryology and a deeper understanding of genetic evolution. It is against this background, and by combining data from anatomical embryology, early fetal myocardial function, and fetal blood flow with a new understanding of the genetically modular development of cardiac chambers (the independent, regional development of cardiac chambers under distinct genetic control) that the ballooning model of heart development1 has revolutionised our understanding of normal heart development.

The evolution of endothermic physiology required the efficiency of a four-chambered heart, with two parallel but separate circulations: systemic and pulmonary. The complexity of its development from a single heart tube in the very early fetus allows for little redundancy, and relatively small lesions may compromise metabolic efficiency severely, leading to heart disease and early death. It seems reasonable to assume that most, if not all, congenital heart disease (CHD) stems from errors in the genetic control of heart development, and that the understanding of these controlling molecular mechanisms may allow us to understand the origins of CHD. And with understanding comes the potential of prevention and possibly even early repair.

Some questions arise, however

• If all cells have essentially exactly the same DNA, how is differentiation during development controlled? A nerve cell is fundamentally different from a right ventricular myocyte, which differs markedly from a cell in the sino-atrial node!

• The birth incidence of CHD is approximately 8/1 000, of which 80% is sporadic (non-syndromic): if sporadic CHD is usually not associated with known DNA changes (and is therefore rarely familial) then why do some developmental processes result in CHD?

• How do teratogens cause the genetic mistakes that lead to CHD?

• In contrast, how does folate decrease the incidence of CHDs? In Fig. 1 the significant decrease in the incidence of severe CHD followed the introduction of mandatory folate fortification of all flour and pasta in Quebec in 1998.2


The startling decrease in CHD incidence in Quebec, possibly due to folate supplementation, hints at an environmental factor which has an immediate and direct effect on the control of cardiac development without altering the DNA sequence: this is epigenetics. It smacks of witchcraft, but how is it possible?

Epigenetics: a fresh look at developmental control

A recent definition: epigenetics is ‘the molecular factors and processes around DNA that regulate genome activity independent of the DNA sequence and that are mitotically and meiotically stable.’3 In other words, the controlling process of DNA transcription and replication may be as important as the actual base pair sequence per se. If the mechanism of control is altered or defective, it may result in serious developmental errors such as CHD. Skinner comments: ‘The paradigm that genetics is the primary factor to regulate developmental biology is limited and ignores the plasticity to respond rapidly to environment, nor does it explain abnormal development and disease etiology in the absence of genetic alterations.’4

The control of heart development is primarily the function of the T-box transcription factors. These factors directly control gene transcription, but in addition are intimately linked to developmental processes through interactions with epigenetic control complexes. The complexes alter chromatin and histones in a dizzying symphony of modifying and remodelling factors that in turn activate and repress DNA transcription. Teratogenic or other modifications of these (epigenetic) controlling mechanisms can lead to CHD without causing any changes of the DNA sequence. Epigenetic modification may therefore result in a non-mutagenic alteration of the phenotype, potentially causing a heart lesion.

Evidence of the direct links between these gene transcription controls and environmental factors such as teratogens (ethanol, lithium, homocysteine, etc.) is now rapidly accumulating. Simultaneously, the role and mechanism of folate protection against CHD by the epigenetic manipulation and control of developmental pathways is coming to light.

Should it become clear that a significant number of congenital heart lesions are indeed due to altered epigenetic control of DNA transcription, thereby leading to maldevelopment, the potential exists that these mechanisms are targets of future preventive or therapeutic interventions.

DNA, we thought, was an iron-clad code that we and our children and their children had to live by. Now we can imagine a world in which we tinker with DNA, bend it to our will. It will take geneticists and ethicists many years to work out all the implications, but be assured: the age of epigenetics has arrived.

John Cloud, Time, January 2010.

References
1. Moorman AFM, Christoffels VM. Cardiac chamber formation: development, genes, and evolution. Physiol Rev 2003;83:1223-12672.

1. Moorman AFM, Christoffels VM. Cardiac chamber formation: development, genes, and evolution. Physiol Rev 2003;83:1223-12672.

2. Ionescu-Ittu R, et al. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ 2009;338:b1673.

2. Ionescu-Ittu R, et al. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ 2009;338:b1673.

3. Skinner MK, et al. Epigenetic transgenerational actions of environmental factors in disease etiology. Trans Endocrinol Metab 2010;21:214-222.

3. Skinner MK, et al. Epigenetic transgenerational actions of environmental factors in disease etiology. Trans Endocrinol Metab 2010;21:214-222.

4. Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth Defects Res C Embryo Today 2011;93:51-55.

4. Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth Defects Res C Embryo Today 2011;93:51-55.

Further reading
    Gilbert SF, Epel D. Ecological development biology: integrating epigenetics, medicine and evolution. Sinauer: Sunderland, 2009. (A book that meshes these three fields beautifully.)


Fig. 1.The significant decrease in the incidence of severe CHD in Quebec after mandatory fortification of grain products in 1998. 2

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