By Grace Langley
As a young scientific community, there is a lot of interest and awareness focused on genetics, and for good reason! The future of biological science appears to be rooted in the mysteries of DNA: with CRISPR and personalised medicine the technologies of the future. However, our genetic material is not just the genes first explored by Mendel in the mid-19th century, nor is it so simple as a seemingly endless sequence of the four different nitrogenous bases. In eukaryotes genetic material is associated with proteins called histones. Epigenetics is a progressive field that explores not only changes to DNA, but also changes to the chemistry of histones, and the effect that this has on gene expression.
The Definition of Epigenetics
The definition of epigenetics is a complex subject, and was the subject of many articles in its own right in the 20th century. In order to understand what epigenetics is, we have to fully understand a molecular structure known as the nucleosome. The nucleosome is a structure that consists of a section of DNA, wound around eight histone proteins. Many nucleosomes packed tightly together form chromatin. At its most basic, epigenetics is a series of chemical changes to DNA and the associated nucleosome.
However, it is vital to understand that an epigenetic change to genetic material is not the same as a mutation in DNA. In a genetic mutation, the base sequence of DNA is altered and this has varying results on the health of the cell. However,with an epigenetic modification, there is no change to the sequence of nitrogenous bases. This means that the four nitrogenous bases, adenine, cytosine, guanine and thymine, remain in the same order no matter what changes occur in the epigenome. So what makes epigenetics so exciting?
Scientists have long been baffled by the effect of the environment on physical characteristics. How can an environmental factor like the availability of milk influence the height of organisms many generations later? The answer, of course, lies in epigenetics. While environmental factors very rarely affect the genome of an organism, save for exposure to carcinogens, the epigenome takes on this role. Through a variety of metabolic pathways, the nucleosome undergoes a series of structural changes in response to a change in environmental conditions. We will explore the mechanisms that cause these structural changes later in the article: however, these epigenetic modifications do have a direct influence on the genome, partly controlling the expression of genes and thus influencing proteome/phenotype depending on whether the genes are exons or introns.
One of the largest areas of interest in current epigenetic research is the heritability of the epigenome. In other words, some epigenetic modifications (but not all) can be inherited by later generations. This is known as transgenerational heritability and has many important scientific implications, especially when the influence of the environment on epigenomes is a forethought. Consider an environmental impact that caused an epigenetic modification in your grandfather may still be affecting you today and may affect your future children too even though the nucleotide sequence in your DNA is unchanged. The hereditary nature of the epigenome is certainly worth thorough scientific investigation and reading for those interested- like you and me.
The Mechanisms by which the Epigenome Influences Cellular Function
Unlike the genome, the epigenome can vary between cells without causing any danger to health. This is vital for the biological function of multicellular eukaryotes, especially large ones like humans, as it means that we can have specialised cells that perform one function very well without wasting resources on unneeded proteins. This is because the epigenome plays a fundamental part in the regulation and control of gene expression, thus allowing certain cells to express a gene more frequently than others. A good example of this is the glandular tissues of the human body whose sole purpose is to produce a protein (e.g. hormones in the endocrine system). These cells need to undergo large amounts of protein synthesis of a particular protein, and thus the exons and gene that encodes this protein needs to be expressed more frequently in these cells than in other tissues. Wouldn’t it be strange if your skin cells produced just as much pancreatic amylase as your pancreatic tissues? External digestion is certainly interesting...but not very desirable as a human.
But how does the epigenome regulate gene expression?
The first example of an epigenetic modification mechanism is one of the cornerstones of epigenetic discovery: DNA methylation. DNA methylation is a simple chemical mechanism where a methyl group is added to a cytosine base. This does not change the base sequence of the genome, but it does repress the transcription of that gene, a stage in protein synthesis, meaning that the rate of expression of the gene where the methylation takes place is reduced. DNA methylation is a process often associated with aging, but there are many more similar chemical processes that affect DNA and are considered part of the epigenome: phosphorylation, glycation and acetylation to name a few.
However, it is not just DNA that can undergo epigenetic modification, the histones can also play a part in the wider epigenome. As previously mentioned, the nucleosome consists of eight histones with a section of DNA wound around it that condenses to form chromatin and chromosomes during mitosis/meiosis. What is new about this concept is that the way the nucleosomes condense into chromatin can affect the rate at which a particular gene is expressed. In fact, there are two different types of chromatin differentiated by how the nucleosomes condense. The first is euchromatin, which is where the DNA is not wound as tightly around the histone proteins, and the second is heterochromatin. Heterochromatin is when the DNA molecule is wound tightly around the histone molecule, meaning that nucleosomes are packed in close together, creating a dense form of chromatin. Furthermore, in this form of chromatin, the genes are less accessible for enzymes, preventing protein synthesis or expression of these genes. Any genes in a section of heterochromatin are expressed at a lower rate than genes in a section of euchromatin. The areas of the genome that are in each form of chromatin is variable both over time and between cells, so this is a form of epigenetic modification, and allows eukaryotic genomes to regulate the expression of genes across time (for example as may be required by the cell cycle) and between cells.
The Future of Understanding Epigenetics
The future of understanding epigenetics is certainly in good hands, and while some scientists may focus on the mechanisms of transgenerational heritability of epigenetic modifications others are exploring the metabolic processes that lead to an epigenetic modification in the first place. This is a particularly interesting direction for research to head as it explores in more detail how changes in the environment affect the epigenome including the idea that metabolism directly communicates environmental changes to the chromatin state. (1.) Further exploration of the modification of the epigenome is helping to uncover fundamental cellular mechanisms which we could not previously identify.
The potential of epigenetic research in the future is exciting, with implications for immunology, cell differentiation and cancer research. In the case of cancerous cells, some epigenetic modifications caused by metabolic reactions can influence tumour progression or suppression, which has clear implications for the future as the suppression of tumours would certainly increase the probability of treatments being successful.
Understanding the basic structure of DNA was just the beginning of a long road for biologists and chemists alike: but the future of epigenetics will hopefully help us understand in more detail the complexities of gene expression and the influence of the environment on how our DNA is presented in phenotypes.
References:
Dai, Z., Ramesh, V., & Locasale, J. W. (2020). The evolving metabolic landscape of chromatin biology and epigenetics. Nature Reviews Genetics, 21(12), 737–753. https://doi.org/10.1038/s41576-020-0270-8
Bird, A. (2007). Perceptions of epigenetics. Nature, 447(7143), 396–398. https://doi.org/10.1038/nature05913