The Role of DNA Methylation in Hypertension

Abstract

DNA methylation is the covalent modification of DNA that affects its function, without altering DNA sequences. Three important roles of DNA methylation include intrauterine programming, acquired predisposition, and transgenerational inheritance. A wide variety of factors can affect DNA methylation. Intrauterine programming involves drastic changes in DNA methylation patterns during cellular development and differentiation, which have a long-lasting effect on the predisposition of offspring. Influences from the mother, including maternal nutritional status, modify intrauterine epigenetic programming. In contrast to the rapid and drastic changes in utero, postnatal factors in daily life can also continue to slowly and dynamically change DNA methylation patterns in both somatic and germ cells. Epigenetic changes occurring in germ cell DNA exert a transgenerational impact on the phenotype of future generations, thus providing a means for ancestral transmission of environmental experiences. Despite adaptive ability, mismatch effect of transgenerational inheritance could be potentially harmful to health if environment has changed, and the acquired acclimatization is no longer beneficial. Increasing evidence from both human and animal studies indicates that DNA methylation exerts a causal impact on the development of hypertension. Therefore, an adverse outcome of maternal malnutrition could be the development of hypertension in offspring, whereby nutritional factors or disease conditions could induce phenotypes susceptible to hypertension through alteration of DNA methylation patterns. These factors are likely to alter DNA methylation patterns in all tissues including germ cells, and despite no direct evidence of an association between transgenerational epigenetic inheritance and hypertension, it is likely to play a role.

Genetic Programming of Hypertension

“…Furthermore, the offspring rats showed impaired endothelial relaxation, consistent with the fact that Panx1 encodes a hemichannel that plays a role in endothelial relaxation ( 67 ). These findings suggest that in utero nutritional status may affect childhood BPs; however, further research will be needed to determine whether prenatal and postnatal nutritional status have effects on the development of HTN in children ( 68 ).…”

Novel methylation mark and essential hypertension

“…Pathway for active DNA demethylation involves ten-eleven-translocases (TET) family (Fig. 3) of proteins [27] that converts 5mC to 5-hydroxymethlycytosine (5hmC) and further to 5-formylcytosine (5fC) which subsequently is oxidised to form 5-carboxylcytosine (5caC) [1,28]. These TET dependant oxidation products are considered as demethylation intermediates of 5mC playing crucial role in transcription, chromatin remodelling and DNA repair [29].…”

“…These TET dependant oxidation products are considered as demethylation intermediates of 5mC playing crucial role in transcription, chromatin remodelling and DNA repair [29]. Both 5fC and 5caC are recognized and excised by thymine-DNA glycosylase (TDG) resulting in replacement by unmodified cytosine [1]. Effect of DNA methylation on gene expression is vastly studied in relation to cancer but its role with context to hypertension has recently gained interest.…”

“…Hypertension, more commonly known as high blood pressure, occurs due to constantly high pressure on the walls of blood vessels. It is broadly classified into primary and secondary where primary or essential hypertension (EH) is more prevalent form affecting around 95% of adult patients having high blood pressure [1]. Primary hypertension is one which occurs without any known identifiable cause whereas secondary hypertension occurs secondarily to certain other primary ailment.…”

“…Genome-wide association studies (GWAS) have identified different genetic loci to be associated with hypertension [8][9][10][11]. These genetic loci accounts for small fraction of heritability highlighting either the cumulative effect of such polymorphisms or role of some other non-genetic factor (epigenetic mechanisms) that can be modified through lifestyle or environmental factors [1] for disease outcome. This led to epigenome-wide association studies (EWAS) where DNA methylation at different CpG sites was found to be associated with blood pressure in individuals from varied ancestry [12,13].…”