Epigenetics

Epigenetics is the study of a group of mechanisms that affects how genes are ‘read’ by cells. It's the term used to explain how a gene expresses an organism’s characteristics (active versus inactive genes) and to what degree.

Epigenetics is akin to “directing”—it orchestrates how genes work, which shapes the behavior of all organisms. It also describes heritable changes in gene expression that do not involve changes to the underlying DNA—a change in phenotype without a change in genotype—which in turn affects how cells read the genes.

In recent years, the notion of epigenetics has expanded as some studies have found that environmental factors, such as diet, exercise, climate change, psychological trauma, etc., can also drive the expression of certain genes. Some have controversially taken this to mean that epigenetics means that nurture (environment) has more influence than heredity and nature (genes and gene expression).

At least four systems—methylation, non-coding RNA (ncRNA)-associated gene silencing, histone modifications and chromatin remodeling of DNA—are currently considered to initiate and sustain epigenetic change.

Why is epigenetics important?

Epigenetic change is a regular and natural occurrence. It helps describe the impact of what we eat, where we live, who we interact with, when we sleep and how we exercise—all of these cause chemical modifications around the genes that will amplify their effects or turn those genes on or off over time.

Epigenetic modifications can manifest as commonly as the manner in which cells differentiate to end up as skin cells, liver cells, brain cells, etc. Additionally, in the case of certain diseases such as cancer or Alzheimer’s, various otherwise healthy genes could be switched into an opposite state, leading to the expression of a disease.

If we could understand how these processes work, theoretically we could reverse the gene’s state to keep the positive impacts while eliminating the consequences of deleterious gene activity. Some human epidemiological studies have provided evidence that prenatal and early postnatal environmental factors influence the adult risk of developing various chronic diseases and behavioral disorders without changing the germline (sperm and egg). With the knowledge of how epigenetics works, we could theoretically reduce incidences of cancer, slow aging, reduce obesity and much more.

Epigenetics also makes us behaviorally unique. Although we are all human, some of us have blonde hair or darker skin or are taller. Some of us hate the taste of mushrooms or eggplants or Brussel sprouts. Some of us are more sociable than others. Our genetic differences as well as the different combinations of genes that are turned on or off contribute to what makes each of us unique—and theoretically we can control them far more than was once believed.

Are epigenetic changes heritable?

The field of epigenetics has expanded in recent years to address whether DNA changes derived from environmental exposures lead to transgenerational inheritance—from parent to offspring and possibly to future generations. For example, descendants of malnourished women from the Dutch famine of 1944-45 showed evidence in their epigenome (collection of epigenetic markings on a person’s genome) of the traumatic event—increased rates of schizophrenia, coronary heart disease and obesity compared to those not exposed to famine.

Limited data from epidemiological studies support the phenomenon of transgenerational inheritance of epigenetic markings. However, others argue that what appear to be germline changes are not due to epigenetics. Instead, the changes are actually the result of genetic variation (rather than expression) from person to person. Yet some experts believe that epigenetic changes are the artifacts or consequence of other processes, meaning that targeting them or ‘fixing them’ won’t change a person’s health.

In organisms like plants, the data are far more robust that acquired epigenetic changes can be passed onto future generations. The ongoing debate over the significance of epigenetics and the role it plays in humans and all life on earth makes it one of the most exciting fields of study in science.

What is DNA methylation?

Humans have 19,000+ genes and need all of those genes working in synchrony to make you you. But not every cell needs to express every one of those genes.

Your brain, for example, needs about a third of them to function properly. So, what do the cells of your brain do with the other two thirds of the genes?

One option is to silence genes and regions of the genome not needed by adding a methyl group to them in a process called methylation. A methyl group is a tiny molecule composed of a carbon and three hydrogens. While the influence of one methyl is small, the additive effect of many methyl groups can block the normal machinery of the cell from accessing the genome and thereby effectively shut the gene off. Methyl groups are added to DNA, but they also can be added to RNA or proteins.

The process is not merely about the turning on and off of genes, though. Methyl groups also can change the expression of the piece of DNA where they are added. More specifically, methylation turns the expression of that gene down, meaning that less protein will be made from the methylated gene as compared to an unmethylated copy of the same gene.

A hypermethylated gene may produce no protein, while a hypomethylated (under) gene may produce a lot of the protein, having dramatic effects on the appearance, physiology, behavior and functioning of the individual. Methylation, therefore, is a process that is not only fundamental to gene expression in the cell, but also as a cornerstone of the modern understanding of epigenetics.

One of the central questions in research currently is the role methylation plays at the interface of gene expression and the environment. Data are mounting that the environment can influence the coverage and placement of methyl groups on particular regions of the genome. For example, differences in methylation patterns are one reason why identical twins grow up to be such different individuals. The pattern of methyl groups on the DNA of a pair of 3-year-old twins is almost identical. But as the twins age, the patterns of methyl groups on their respective genomes begin to diverge due to the effects of their different environments—in turn changing their gene expression and subsequently their behavior, appearance and physiology.

What is non-coding RNA (ncRNA)-associated gene silencing?

The central dogma of biology states that “DNA makes RNA and RNA makes protein.” DNA is transcribed into messenger RNA, and the “mRNA” is translated into protein. The overall process is less complicated than it sounds. DNA has the information on how to make an organism, and proteins are the functional and structural molecules of cells—with a type of RNA (messenger or mRNA) playing the middle man. And for decades that’s how we thought molecular biology worked: as a one-way street.

However, we have since learned that the relationship between DNA and RNA is more complicated. Many RNA molecules in the cell do not encode proteins. These are categorized as non-coding RNA (ncRNA) or functional RNA, which means that their job in the cell is performed by the RNA molecule itself.

Within this family of non-coding RNA are several types of small RNAs, a key component of epigenetics that can alter gene expression. This family of RNA was discovered more than a decade ago (small RNAs were chosen as the “Breakthrough of the Year” by Science magazine in 2002), but there is still much to be understood about how they work.

Researchers discovered the role of small RNAs in modulating or actually shutting down the translation of specific sets of genes into proteins in petunia flowers and later in the model organism C. elegans, a tiny, transparent worm. One type of small RNA, called a microRNA, occurs naturally in our cells and acts as a “dimmer switch,” dampening translation of specific sets of proteins from the messenger RNAs that encode them. Another type of RNA, called a “small interfering RNA,” is synthesized in a lab and introduced into cells, where it blocks translation of specific proteins. Harnessing the power of small noncoding RNAs may provide news types of biomarkers to aid diagnosis as well as drugs.

What is histone modification and chromatin remodeling?

What does the DNA in your cells look like? The double helical DNA is wound tightly, over and over again—in large part, so that it can fit into the cells—around proteins called histones. Many histones together are referred to as chromatin. Each of our 70 trillion or so cells (minus cells without genomic information like red blood cells) must each pack in 6 feet of DNA.

If our DNA were not condensed, one chromosome would measure roughly 5 centimeters long—the length from our ring finger knuckle to the end of a nail—and that’s just one of them. There’s another 45 (23 pairs) that would need to fit into each cell too. It’s because of the organization around histone proteins that DNA can fit inside our cells.

A second role of chromatin structure is in determining how many of the genes are expressed. In general, in regions of tight winding (called heterochromatin) local genes are more compact and their expression lower, whereas genes in loosely wound DNA (called euchromatin) are more accessible to the expression machinery. Which DNA is wound tightly or loosely changes in response to environmental factors and signals. The changes in the chromatin from tight to loose (or vice versa) are called chromatin remodeling. Like other epigenetic factors, chromatin has a huge influence on which genes are being expressed and the extent to which they are expressed.

The effect of histone modifications results from the sum of many different placements occurring at once, rather than a single tag in isolation. This complicated process of which histones bind where along the DNA is referred to as the histone code.

The degree to which histone modifications are an epigenetic process is under intense debate. Some evidence suggests that environmental triggers (like diet or stress) can influence the arrangement of histones. Evidence from model organisms and limited data from humans suggest that some histone modifications may be passed on to the next one or few generations. However, no mechanism has been proposed for how this could occur and the idea is controversial in the scientific community.

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