The genetic information for an organism is encoded in the DNA of the organism's chromosomes, but there are other influences at work. The DNA sequences making up a gene may not be active, or they may be blocked. An organism's characteristics are determined by its genes, but whether the genes are actually creating the encoded characteristic is called gene expression.
Many factors can influence gene expression, determining whether the gene produces its characteristic at all or sometimes only weakly. When gene expression is influenced by hormones or enzymes, the process is called gene regulation.
Epigenetics studies the molecular biology of gene regulation and the other epigenetic influences on gene expression. Basically any influence that modifies the effect of DNA sequences without changing the DNA code is a subject for epigenetics.
Epigenetics: Definition and Overview
Epigenetics is the process through which genetic instructions contained in the DNA of organisms are influenced by non-genetic factors. The primary method for epigenetic processes is control of gene expression. Some control mechanisms are temporary but others are more permanent and can be inherited via epigenetic inheritance.
A gene expresses itself by making a copy of itself and sending the copy out into the cell to produce the protein encoded in its DNA sequences. The protein, either alone or in combination with other proteins, produces a specific organism characteristic. If the gene is blocked from producing the protein, the organism characteristic will not appear.
Epigenetics looks at how the gene can be blocked from producing its protein, and how it can be switched back on if it is blocked. Among the many epigenetic mechanisms that can influence gene expression are the following:
- Deactivating the gene.
- Stopping the gene from making a copy.
- Stopping the copied gene from producing the protein.
- Blocking the protein's function.
- Breaking up the protein before it can work.
Epigenetics studies how genes are expressed, what influences their expression and the mechanisms that control genes. It looks at the layer of influence above the genetic layer and at how this layer determines epigenetic changes in what an organism looks like and how it behaves.
How Epigenetic Modification Works
Although all cells in an organism have the same genome, the cells take on different functions based on how they regulate their genes. On an organism level, organisms may have the same genetic code but look and behave differently. In the case of humans for example, identical twins have the same human genome but will look and behave slightly differently, depending on epigenetic alterations.
Such epigenetic effects can vary depending on many internal and external factors, including the following:
- Growth factors
- Transcription factors
- Chemical stimuli
- Environmental stimuli
Each of these can be epigenetic factors that promote or disrupt gene expression in the cells. Such epigenetic control is another way to regulate gene expression without changing the underlying genetic code.
In each case, overall gene expression is changed. The internal and external factors are either required for gene expression, or they may block one of the stages. If a required factor such as an enzyme needed for protein production is absent, the protein can't be produced.
If a blocking factor is present, the corresponding gene expression stage can't function, and the expression of the relevant gene is blocked. Epigenetics means that a trait that is encoded in the DNA sequences of a gene may not appear in the organism.
Epigenetic Limitations to DNA Access
The genome is encoded in thin, long molecules of DNA sequences that have to be wound tightly in a complicated chromatin structure to fit into tiny cell nuclei.
To express a gene, the DNA is copied via a transcription mechanism. The part of a DNA double helix that contains the gene to be expressed is unwound slightly and an RNA molecule makes a copy of the DNA sequences making up the gene.
The DNA molecules are wound around special proteins called histones. The histones can be changed so that the DNA is wound more or less tightly.
Such histone modifications can result in DNA molecules being wound so tightly that the transcription mechanism, made up of special enzymes and amino acids, can't reach the gene to be copied. Limiting access to a gene through histone modification results in epigenetic control of the gene.
Additional Epigenetic Histone Modifications
In addition to limiting access to genes, histone proteins can be changed to bind more or less tightly to the DNA molecules wound around them in the chromatin structure. Such histone modifications affect the transcription mechanism whose function is to make an RNA copy of the genes to be expressed.
Histone modifications that affect gene expression in this way include the following:
- Methylation - adds a methyl group to histones, increasing binding to DNA and reducing gene expression.
- Phosphorylation - adds phosphate groups to histones. The effect on gene expression depends on interaction with methylation and acetylation.
- Acetyleation - histone acetylation reduces binding and upregulates gene expression. The acetyl groups are added with histone acetyltransferases (HATs).
- De-acetylation - removes acetyl groups, increases binding and reduces gene expression with histone deacetylase.
When histones are changed to increase binding, the genetic code for a specific gene can't be transcribed, and the gene is not expressed. When binding is reduced, more genetic copies can be made, or they can be made more easily. The specific gene is then expressed more and more of its encoded protein is produced.
RNA Can Interfere with Gene Expression
After the DNA sequences of a gene are copied to an RNA sequence, the RNA molecule leaves the nucleus. The protein encoded in the genetic sequence can be produced by small cell factories called ribosomes.
The chain of operations is as follows:
- DNA transcription to RNA
- RNA molecule leaves the nucleus
- RNA finds ribosomes in the cell
- RNA sequence translation to protein chains
- Protein production
The two key functions of an RNA molecule are transcription and translation. In addition to the RNA used to copy and transfer the DNA sequences, cells can produce interference RNA or iRNA. These are short strands of RNA sequences called non-coding RNA because they don't have any sequences that encode genes.
Their function is to interfere with transcription and translation, reducing gene expression. In this way, iRNA has an epigenetic effect.
DNA Methylation Is a Major Factor in Gene Expression
During DNA methylation, enzymes called DNA methyltransferases attach methyl groups to DNA molecules. To activate a gene and start the transcription process, a protein has to attach to the DNA molecule near the start. The methyl groups are placed at the locations where a transcription protein would normally attach, thus blocking the transcription function.
When cells divide, the DNA sequences of the cell's genome are copied in a process called DNA replication. The same process is used to create sperm and egg cells in higher organisms.
Many of the factors that regulate gene expression are lost when the DNA is copied, but a lot of the DNA methylation patterns are replicated in the copied DNA molecules. This means that the regulation of gene expression caused by DNA methylation can be inherited even though the underlying DNA sequences remain unchanged.
Because DNA methylation responds to epigenetic factors such as environment, diet, chemicals, stress, pollution, lifestyle choices and radiation, the epigenetic reactions from exposure to such factors can be inherited through DNA methylation. This means that, in addition to genealogical influences, an individual is shaped by the behavior of the parents and the environmental factors to which they were exposed.
Epigenetics Examples: Diseases
Cells have genes that promote cell division as well as genes that suppress rapid, uncontrolled cell growth such as in tumors. Genes that cause the growth of tumors are called oncogenes and those that prevent tumors are called tumor suppressor genes.
Human cancers can be caused by the increased expression of oncogenes coupled with the blocked expression of tumor suppressor genes. If the DNA methylation pattern corresponding to this gene expression is inherited, the offspring may have an increased susceptibility to cancer.
In the case of colorectal cancer, a faulty DNA methylation pattern may be passed on from parents to offspring. According to a 1983 study and paper by A. Feinberg and B. Vogelstein, the DNA methylation pattern of colorectal cancer patients showed increased methylation and blocking of tumor suppressor genes with a decreased methylation of oncogenes.
Epigenetics can also be used to help treat genetic diseases. In Fragile X Syndrome, an X-chromosome gene that produces a key regulatory protein is missing. The absence of the protein means that the BRD4 protein, which inhibits intellectual development, is produced in excess in an uncontrolled fashion. Drugs which inhibit the expression of BRD4 can be used to treat the disease.
Epigenetics Examples: Behavior
Epigenetics has a major influence on disease, but it can also affect other organism traits such as behavior.
In a 1988 study at McGill University, Michael Meany observed that rats whose mothers cared for them by licking and paying attention to them developed into calm adults. Rats whose mothers ignored them became anxious adults. An analysis of brain tissue showed that the behavior of the mothers caused changes in the methylation of brain cells in the baby rats. The differences in rat offspring were the result of epigenetic effects.
Other studies have looked at the effect of famine. When mothers were exposed to famine during pregnancy, as was the case in Holland in 1944 and 1945, their children had a higher incidence of obesity and coronary disease compared to mothers not exposed to famine. The higher risks were traced to reduced DNA methylation of a gene producing an insulin-like growth factor. Such epigenetic effects can be inherited over several generations.
Effects from behavior that may be transmitted from parents to children and onward can include the following:
- Parent diet can influence offspring mental health.
- Environmental exposure to pollution in parents can affect child asthma.
- Mother nutrition history can affect infant birth size.
- Consumption of excess alcohol by the male parent may cause aggression in offspring.
- Exposure of parents to cocaine may affect memory.
These effects are the results of changes in DNA methylation passed on to offspring, but if these factors can change DNA methylation in parents, the factors that the children experience can change their own DNA methylation. Unlike the genetic code, DNA methylation in children can be changed by behavior and environmental exposure in later life.
When DNA methylation is affected by behavior, the methyl marks on DNA where the methyl groups may attach can change and influence gene expression in that way. Although many of the studies dealing with gene expression date from many years ago, it is only more recently that the results have been connected to a growing volume of epigenetic research. This research shows that the role of epigenetics may be as powerful an influence on organisms as the underlying genetic code.
- Gerstner Sloan Kettering School of Biomedcal Sciences: What Is Epigenetics, and Why Is Everyone Talking about It?
- Harvard University: Early Experiences Can Alter Gene Expression and Affect Long-Term Development
- Lloma Linda University: Epigenetic Research Reveals Changes in Cellular Functions
- University of Utah: Epigenetics and Inheritance