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Year : 2020  |  Volume : 58  |  Issue : 2  |  Page : 90-93

Epigenetics: The Interplay of Nature and Nurture

RK Eye Care Centre, Rasipuram, Tamil Nadu, India

Date of Submission22-Dec-2019
Date of Acceptance06-Jan-2020
Date of Web Publication17-Jun-2020

Correspondence Address:
Dr. R Vasumathi
RK Eye Care Centre, Rasipuram - 637 408, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjosr.tjosr_124_19

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Epigenetics is the regulation of gene expression through alterations in DNA or associated factors other than the DNA sequence. These regulatory processes control the transcription of information encoded in the DNA sequence into RNA before their translation into proteins. Unlike DNA sequence, which is largely fixed throughout the lifecourse, epigenetic patterns not only vary from tissue to tissue but alter with advancing age and are sensitive to environmental exposures. It is this propensity for change that makes epigenetic processes the focus of such interest, as they lie at the interface of the environment and co-ordinated transcriptional control. These factors control the diverse manifestations of diseases. Insights into epigenetic modification may lead to new therapies for common diseases. This article gives a brief overview of the epigenetic mechanisms and their role in some of the common eye diseases.

Keywords: DNA methylation, epigenetics, gene expression, histone modification

How to cite this article:
Vasumathi R. Epigenetics: The Interplay of Nature and Nurture. TNOA J Ophthalmic Sci Res 2020;58:90-3

How to cite this URL:
Vasumathi R. Epigenetics: The Interplay of Nature and Nurture. TNOA J Ophthalmic Sci Res [serial online] 2020 [cited 2021 Dec 3];58:90-3. Available from: https://www.tnoajosr.com/text.asp?2020/58/2/90/286931

  Introduction Top

The Human Genome Project found that the protein-coding DNA accounted for only 2% of the entire genome and, thus, proposed that some noncoding regions, such as capable of producing noncoding RNA, repeat fragments, and transposons, may also exercise certain functions. Moreover, the development of some diseases cannot be explained solely by the change in DNA sequence; other factors, including living environment, mental conditions, and stress, may also play a vital role in the onset of diseases. Thus, the term epigenetics refers to heritable modifications that are not involved in the changes in the DNA sequence. One example of an epigenetic change in eukaryotic biology is the process of cellular differentiation.[1] During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell, the zygote, continues to divide, the resulting daughter cells change into all the different cell types in an organism, including neurons, muscle cells, epithelium, and endothelium of blood vessels, by activating some genes when inhibiting the expression of others.

Although our epigenetic marks are more stable during adulthood, they are still thought to be dynamic and modifiable by lifestyle choices and environmental influence.[2] It is becoming more apparent that epigenetic effects occur not just in the womb, but over the full course of a human life span, and that epigenetic changes could be reversed. There are numerous examples of epigenetics that show how different lifestyle choices and environmental exposures can alter marks on the top of DNA and play a role in determining health outcomes.

  Mechanisms of Epigenetic Modification Top

The four mechanisms of epigenetic modification are discussed below.[3]

  DNA Methylation Top

DNA methylation is the earliest discovered mechanism in epigenetic modification. It refers to the addition of methyl groups of S-adenosylmethionine (SAM) to DNA molecules catalyzed by DNA methyltransferase. In mammalian cells, cytosine–phosphate–guanine (CpG) exists mainly in two forms: one evenly distributed throughout the DNA sequences (60%–90% are methylated) and the other grouped in clusters known as the CpG islands (generally protected and remain unmethylated). In the eukaryotic cells, CpG islands are often found in the regulatory regions of coding genes and are involved in gene expression and chromatin structure modification.[4] DNA methylation deactivates the target genes or causes conformational changes in DNA, thereby affecting the protein–DNA interaction. In a human body, there are three states of DNA methylation: persistent hypomethylation, induced demethylation, and hypermethylation. The states of methylation are closely related to disease development; persistent hypomethylation and hypermethylation are found in some cancer cells.

  Histone Modification Top

Histone modifications refer to methylation, acetylation, phosphorylation, adenylation, ubiquitination, ADP-ribosylation, and other modifications of histones in the presence of related enzymes. Histones are an integral part of epigenetics. Histone modification affects the transcriptional activity of genes, thereby playing a significant role in regulating DNA transcription, repair, and replication, as well as alternative splicing and chromosome condensation.[4]

  Noncoding RNA Top

Noncoding RNA refers to RNA molecules that do not encode proteins. miRNA is a single-strand RNA containing 21–25 nucleotides that is involved in posttranscriptional regulation. It can bind to target sequences and modulate the activity of mRNA, mainly by degrading the RNA or suppressing the protein translation.[4] In humans, this process affects 1/3rd of the entire genome, and in mammals, it regulates the expression of >60% proteins. Furthermore, miRNA also participates in various pathological processes, including the inhibition of translation initiation, inhibition of translation, as well as the regulation of mRNA deadenylation and degradation. Each miRNA has multiple target genes, and the same gene can be regulated by different miRNAs. Because the inhibition of protein translation is a critical regulation pathway, the complex mechanism of noncoding RNA realizes the fine regulation of gene expression.

  Chromatin Remodeling Top

Chromatin remodeling refers to epigenetic mechanisms based on altered chromatin conformation. Because the nucleosome is the basic structural unit of chromatin, the remodeling of chromatin primarily involves structural or molecular changes in nucleosomes, histones, and DNAs during the expression, replication, and recombination of genes. Chromatin remodeling can affect DNA methylation, DNA replication, recombination, and repair as well as gene expression.[5]

Although different modification mechanisms affect specific epigenetic phenomena independently, they interact with each other and together determine the complex physiological processes [Figure 1].
Figure 1: Epigenetic mechanisms (Source: National Institutes of Health-http://commonfund. nih. gov/epigenomics/figure. aspx)

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  Epigenetics in Eye Diseases Top

The study of ocular diseases and epigenetic dysregulation is an emerging area of research. In humans, there are several factors that contribute to the increment in all kinds of eye diseases. The prevalence of cataracts, dry eye, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy is steadily increasing year after year for nongenetic reasons. Aging, diet, inflammation, drugs, oxidative stress, and seasonal and circadian changes are impacting on disease prevalence by epigenetics factors, defined as stable heritable traits that are not explained by changes in DNA sequence. The knowledge on the epigenetic alterations may guide therapeutic approaches to have a healthy eye.

  Cataract Top

Cataracts are the result of opacity in the crystalline lens, blocking the transmission of light that reaches the retina. Cataracts may start as early as in 40-year-old individuals and the risk increases with age. It is known that the eye has many protective mechanisms, but they succumb upon sustained challenging by environmental stressors such as electrophilic reactive species, drugs, inflammation, radiation, sunlight, and diabetes.

Klotho gene family seems to be involved in the susceptibility and development of cataracts. In studies performed on cataract models, an age-dependent increased methylation of Klotho's gene promoters has been detected. As a major structural protein component, α-crystallin represents 35% of all crystallins in the lens and it serves as a molecular chaperone to prevent aggregation of other crystallins. Recent studies showed a decreased level of α-crystallin in age-related nuclear cataract. The reduction of α-crystallin expression is linked with the hypermethylation of the CpG island in the CRYAA gene promoter.[6] Moreover, the treatment with DNA-methylation inhibitors results in restoring CRYAA gene expression. Such evidence sustains an epigenetic-based repression of CRYAA in age-related nuclear cataracts. A reasonable therapeutic approach would be the use of inhibitors of the methyltransferase, because in this way, it would be possible to treat this cause of cataracts.

Another epigenetic-based silencing has been reported for a nuclear factor, namely the erythroid 2-related factor 2 (Nrf2). This protein is a transcriptional activator that may protect the lens by binding to antioxidant response elements, which are Cis-acting enhancer sequences in regulatory locus of genes related to detoxification.[7] The results of the analysis performed using age-related cataract crystalline lenses showed a significant demethylation in Keap1 and a decline in Nrf2, these results being similar to the ones found in lenses from a group of patients between 65 and 80 years of age.

  Glaucoma Top

Glaucoma refers to a wide spectrum of ocular conditions with multifactorial etiology distinguished by progressive irreversible optic neuropathy and visual field loss. Risk factors that contribute to glaucoma development are numerous and include increased intraocular pressure (IOP), age, and genetic mutations. Strong evidence shows that predisposing single-nucleotide polymorphisms and environmental effects are also key factors in the development of glaucoma. These reports revealed that abnormal histone acetylation/deacetylation might be related to retinal ganglion cell damage in glaucoma. Various hypotheses have been proposed to explain the link such as that occurrence of polymorphisms at this locus changes the expression of target genes responsible of cell cycle regulation, subsequently inducing retinal ganglion cell apoptosis.

A different aspect of the pathophysiology of glaucoma is the accumulation of extracellular matrix (ECM) in the trabecular meshwork, the conventional pathway of aqueous humor drainage. When the trabecular meshwork is blocked by an abnormal structure in the ECM, aqueous humor does not find a way out and it accumulates within the eye, so IOP increases. Apart from subsequent fibrosis, another relevant finding is the hypoxic environment of the trabecular meshwork of glaucomatous eyes; hypoxia leads to substantial increase in DNA methylation in loci related to the regulation of the expression of the profibrotic (transforming growth factor) β1 factor and the Ras protein activator like 1.[8]

  Ocular Surface Disorders Top

Dry eye is one of the underdiagnosed ocular surface diseases. It has become the most common ocular surface alteration worldwide and it is defined as “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”

Previous studies attributed dry eye to inflammation and the release of proinflammatory cytokines. Recent studies have shown that dry eye may also result due to altered histone methylation pattern. Aging, inflammation, drugs, infections, and ultraviolet exposure may have profound effects on epigenetic modifications and trigger susceptibility to diseases.[9]

  Age-Related Macular Degeneration Top

The pathogenesis of AMD involves genetic and environmental influences. The environmental influences include smoking, obesity, and dietary factors such as antioxidants and dietary fat intake. As such, AMD is a complex, multifactorial disease. These risk factors result in pathologic responses such as inflammation, ischemia, and vascular remodeling, as well as neurodegeneration. Emerging evidence suggests that epigenetic changes are relevant to AMD and as such provide an exciting new avenue of research for AMD. Studies have revealed the impact of posttranslational modification of the genome on the pathogenesis of AMD, such as DNA methylation changes affecting antioxidant gene expression, hypoxia-regulated alterations in chromatin structure, and histone acetylation status in relation to angiogenesis and inflammation.[10] Noncoding RNA-mediated gene regulation also plays a role in AMD at a posttranscriptional (before translation) level. Increasing understanding of the significance of common and rare genetic variants and their relationship to epigenetics and environmental influences may help in establishing methods to assess the risk of AMD. This in turn may allow new therapeutic interventions for the leading cause of central vision impairment in patients over the age of 50 years.

  Effects of Diet and Aging on Epigenetics Top

The epigenome is influenced by environmental factors throughout life. Nutritional factors can have profound effects on the expression of specific genes by epigenetic modification; these may be passed onto subsequent generations, with potentially detrimental effects. For example, it is well known that folate deficiency is associated with open neural tube defects.[11] Because folate is an essential factor in the conversion of methionine to SAM, the main methyl group donor in DNA methylation reactions, dietary deficiency in folate leads to genomic hypomethylation. Other dietary components, such as selenium, arsenic, and polyphenols, may also influence the state of DNA methylation with potential consequences for diseases such as cancer. However, the state of hypomethylation is reversible, because folate therapy was shown to restore DNA methylation to normal levels, correcting the patterns of gene expression administration.[12] The resulting folic acid fortification in foods has resulted in significant reductions in the incidence of open neural tube defects in newborns.

The role of epigenetics in aging is an emerging field of research. It is now known that aged organisms, i.e., those advanced in years, have modified epigenetic signatures. Typically, one observes a decrease in global CpG methylation, coupled with specific regions of hypermethylation, usually in promoter regions. It is hypothesized that such epigenetic changes would result in an altered gene expression profile. Therefore, active investigations continue into potential functional relationships between these epigenetic changes and the disease pathology of common late-onset diseases.[13] Age-related epigenetic differences in humans have been best illustrated through the examination of the epigenome of sets of monozygotic twins.[14] It was found that although twins were epigenetically very similar in early life, older twins exhibited significant differences in DNA methylation. The fact that these differences were more pronounced in twins who had different lifestyles and had spent less of their lives together further highlights the role that environmental factors have in determining the epigenetic signature.

  Conclusion Top

Epigenetics plays an important role in the pathophysiology of numerous ocular diseases. The epigenetic signature is a dynamic entity. Considering the number of elements involved and their various sites of modification, a disruption of the delicate balance in these epigenetic networks by environmental stimuli is a factor in a range of diseases; understanding such changes could open a novel window for therapeutical approaches in addition to current therapies. The field of epigenetics in relation to common complex disease will undoubtedly continue to be the focus of much attention, and its progress will be followed with considerable interest.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007;447:425-32.  Back to cited text no. 1
Alegría-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics 2011;3:267-77.  Back to cited text no. 2
Zhang X, Zhao L, Hambly B, Bao S, Wang K. Diabetic retinopathy: Reversibility of epigenetic modifications and new therapeutic targets. Cell Biosci 2017;7:42.  Back to cited text no. 3
Alkozi HA, Franco R, Pintor JJ. Epigenetics in the eye: An overview of the most relevant ocular diseases. Front Genet 2017;8:144.  Back to cited text no. 4
Santoro R, Grummt I. Epigenetic mechanism of rRNA gene silencing: Temporal order of NoRC-mediated histone modification, chromatin remodeling, and DNA methylation. Mol Cell Biol 2005;25:2539-46.  Back to cited text no. 5
Gu F, Luo W, Li X, Wang Z, Lu S, Zhang M, et al. A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal dominant congenital cataract in a large Chinese family. Hum Mutat 2008;29:769.  Back to cited text no. 6
Liu XF, Hao JL, Xie T, Malik TH, Lu CB, Liu C, et al. Nrf2 as a target for prevention of age-related and diabetic cataracts by against oxidative stress. Aging Cell 2017;16:934-42.  Back to cited text no. 7
McDonnell FS, McNally SA, Clark AF, O'Brien CJ, Wallace DM. Increased global DNA methylation and decreased TGFβ1 promoter methylation in glaucomatous lamina cribrosa cells. J Glaucoma 2016;25:e834-42.  Back to cited text no. 8
Busanello A, Santucci D, Bonini S, Micera A. Review: Environmental impact on ocular surface disorders: Possible epigenetic mechanism modulation and potential biomarkers. Ocul Surf 2017;15:680-7.  Back to cited text no. 9
Gemenetzi M, Lotery AJ. The role of epigenetics in age-related macular degeneration. Eye (Lond) 2014;28:1407-17.  Back to cited text no. 10
Tamura T, Picciano MF. Folate and human reproduction. Am J Clin Nutr 2006;83:993-1016.  Back to cited text no. 11
Ingrosso D, Cimmino A, Perna AF, Masella L, de Santo NG, de Bonis ML, et al. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 2003;361:1693-9.  Back to cited text no. 12
Fraga MF, Esteller M. Epigenetics and aging: The targets and the marks. Trends Genet 2007;23:413-8.  Back to cited text no. 13
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 2005;102:10604-9.  Back to cited text no. 14


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Mechanisms of Ep...
DNA Methylation
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