Epigenetics: Somewhere beyond Mendelian genetics

Edited by Eldrian Tho.

Since Mendel established the basic principles of genetic inheritance in the 1800s through his work on pea plants, genetics has occupied a central position in modern biology as it greatly impacts many everyday aspects of human life. Epigenetics, a subfield of genetics that focuses on how behaviors and environment can cause changes that affect the way that genes work has emerged as a fast-growing research area due to its potential contribution to the study of behaviour, environmental science, cancer, neurobiology and pharmacology by providing extensive explanations for how changes outside of the DNA base sequence can influence the phenotype and how those changes can be heritable.²,⁸ Unlike the classical Mendelian genetics that focuses on the combination of alleles and the variation of inherited characteristics in a particular organism, epigenetics shifts the focus to heritable characteristics caused by reversible changes in gene expression without alterations of DNA base sequence.⁸

In fact, many epigenetic effects are the result of alterations in chromatin structure mediated through mechanisms such as DNA methylation, histone modifications and action of non-coding RNA. ⁸

Figure 1: Mechanism of DNA methylation⁵

DNA methylation is one of the most common mechanisms for epigenetic phenotypes. It involves the addition of a methyl group, predominantly to the cytosine nucleotides that are immediately adjacent to guanine nucleotides (CpG dinucleotide) by DNA methyltransferase (DNMT). DNMT methylates the DNA by transferring methyl group from cofactor S-adenosyl-L-methionine (SAM) to 5’ position of pyrimidine ring of a cytosine residue on DNA to form 5-methylcytosine. The methylation of DNA often leads to repression of transcription in which the presence of the methyl group inhibits binding of transcription factors and other proteins required for transcription to occur. DNA methylation has since been observed to be associated with many human illnesses and health conditions including cancer as DNA methylation potentially leads to uncontrolled cell proliferation by changing the rate of gene expression and inactivating certain important cell processes such as cell cycle regulation, DNA repair, cell adherence, invasion and migration, apoptosis and signaling pathway regulation. According to research, methylation of MSH2 and MLH1 (genes involved in DNA mismatch repair) promoters is responsible for gastric carcinogenesis and development of gastric cancer. Epigenetic changes due to DNA methylation are maintained through replication by DNMT which recognizes the hemimethylated state of CpG dinucleotides and adds methyl groups to the unmethylated cytosine bases. ⁴, ⁸, ¹²

A wide variety of histone modifications have been found to play important roles in the regulation of chromatin state, gene expression and other nuclear events.⁷ Histone modification generally includes addition of phosphate, methyl group, acetyl group and ubiquitin at the positively charged tails of histone proteins which interact with the DNA and affect chromatin structure. The modification of histone can take place at different amino acids on different histones and create many unique potential changes. In general, histone modification mostly alters chromatin structure and affects transcription of genes.⁸ In 2019, some cases of colorectal cancer are detected to be accompanied by abnormal regulation of acetylation on H3K27 and H4K16 (both are core histones) as acetylation of histone modulates a plethora of cell functions such as cell differentiation, nucleosome assembly, change of chromatin structure and stability of gene expression.⁹ The maintenance of epigenetic changes due to histone modifications remains not well understood today although several models have been proposed.⁸

Non-coding RNAs (RNA molecules that are transcribed but not translated)¹¹ are found to bring about modifications of chromatin by a variety of processes. They have been found to regulate DNA methylation levels of nearby genes, either interacting directly with DNMT and preventing methylation or indirectly providing a binding platform for DNMT by forming a DNA: RNA triplex through mediation of de novo methylation. A compelling example of chromatin modifications done by them is X inactivation. A long non-coding RNA known as Xist suppresses transcription on one of the X chromosomes in female mammals by coating one X chromosome and then attracts polycomb repressive complex 2 (PRC2, one of the two classes of polycomb-group proteins which has histone methyltransferase activity and primarily methylates histone H3 on lysine 27) to create H3K27me3 epigenetic mark which alters chromatin structure and represses transcription. Although non-coding RNAs do not encode for proteins, they are found to have imperative roles in cell growth, metabolism, differentiation and proliferation, organismal development and diseases.⁸, ¹¹ According to Shi and the team, non-coding RNAs are found to be associated with physiological and pathophysiological processes of cardiovascular diseases, including coronary heart disease, myocardial infarction and heart failure in recent research. Referring to the research, some of them are closely related to the degree of the injury of myocardial infarction as they are responsible for regulation of cardiac autophagy, cardiac repair and cardiac function development.¹⁰ Up to now, the maintenance of RNA-based epigenetic changes across cell division is still ambiguous.⁸

Obviously, epigenetic alterations could have a variety of effects on human health. To understand how changes in epigenetic marks can be done, epigeneticists have identified several lifestyle factors that might modify epigenetic patterns namely diet, physical activity, environmental pollutants, psychological stress and working habits.¹ The tragedy, the Dutch hunger famine of 1944 is one of the most famous events related to the effects of diet on epigenetics. In 1944, West of Netherlands was starving due to a blockade by Nazi. At that time, most children of pregnant women exposed to famine are found to be smaller in size than normal and suffer from pathologies such as diabetes, obesity, cardiovascular disease and microalbuminuria. Scientists believe that this is due to changes in epigenetics as a result of a lack of food as a constant supply of methyl groups come from amino acids and vitamins are important to attach to a gene that controls production of a growth factor known as insulin-like growth factor (IGF-2).⁵ Nevertheless, epigenetic changes are reversible. Those who suffer from certain adverse epigenetic modifications can practice a healthy lifestyle and re-establish their epigenetic patterns.

It is undeniably true that knowledge of epigenetics has greatly contributed to the medical field. Currently, there are 7 epigenetic drugs approved by the United States Food and Drug Administration (FDA) in cancer therapy to treat hematological malignancies. These epigenetic drugs work by inhibiting specific epigenetic enzymes and reversing the incorporation of an epigenetic mutation.¹³ Apart from therapeutics, epigenetic biomarkers also play an important role in disease diagnosis, prognosis and treatment monitoring. The epigenetic biomarker is able to provide relevant information about the gene function in individual cell types and incorporate information from environment and lifestyle at the same time. In other words, epigenetic biomarker fills the clinical gaps by showing to what extent a specific genetic program is controlled and revealing information about the progression of a disease in an individual from its pathological onset until its resolution.⁶

Following the trend in the development of epigenetics, the future of epigenetics is highly potential due to its reversible nature which makes it an ideal target for therapeutic intervention. Companies such as MRC Technology and AstraZeneca have initiated to discover new epigenetic drug targets for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). They aim to work with academics researching epigenetic mechanisms in this area and achieve fruitful collaboration creating novel small molecule drugs that can target epigenetic pathways for the diseases.³

In the long run of human history, development in the epigenetics field marks our advanced understanding of modern biology. Recent efforts in bioinformatics and dataset collection in the form of human epigenetic enzyme and modulator database and human epigenetic drug database have provided the basis for future discovery and development in epigenetics. Expanding our understanding in epigenetics will allow more research and development to be done in this new field of genetics and unlimited contribution could be brought to us.

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Reference:

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