Epigenetics beyond genes
This topic is sponsored by the Sir Mark Oliphant International Frontiers of Science and Technology Conference Series.
Recent developments in epigenetics suggest that you may inherit more than genes from your parents.
|You will get more from this topic if you have mastered the basics of DNA and genes these links will take you to an annotated list of sites with helpful background information.|
Inside every plant and animal cell the genes provide instructions on how to grow, multiply and function. But not all genes are used at all stages of development, in all types of cells. Epigenetic factors can regulate the amount of gene activity, influencing the growth and appearance of an organism. What's more, epigenetic factors appear to be inherited by the following generations.
Understanding epigenetics is fundamental to understanding how cells work because malfunctions in epigenetic control of gene activity have been implicated in cancer, cardiovascular disease and several inherited genetic conditions.
Types of epigenetic factors
There are several epigenetic ways in which gene activity can be prevented or controlled, including modification of histone proteins, DNA methylation and RNA interference (Box 1: RNA interference and epigenetics). For any of these methods of gene regulation, the absence of the protein product of the gene causes a change in the function or development of the cell.
Role of DNA methylation in regulating gene activity
DNA methylation prevents the expression of genes by altering the amount of messenger RNA. Enzymes attach chemical tags called methyl groups to the bases from which DNA is made. But not all bases in DNA are methylated. The most common site for methylation to occur is a cytosine base followed immediately by a guanine base a combination of base pairs known as a CpG.
The CpG combination of base pairs is relatively rare in most of the human genome, but occurs with unusual frequency at points known as 'CpG islands', which are often found in the promoter region of genes. Promoter regions are found at one end of a gene and control the level of gene activity.
The tagging of CpGs in promoter regions with methyl groups decreases the amount of RNA made from the gene, so it is said to 'silence' the gene. In normal cells, promoter regions are mostly free of methylation, while CpGs outside the promoter region are almost always methylated.
DNA methylation in plants
DNA methylation in plants is more diverse than in animals. In addition to methylating CpGs, plants also methylate the cytosine at CpNpG and CpNpNp sequences, where N can be any base. Plants also have a greater variety of enzymes involved in methylating DNA than animals. Methylation of plant DNA occurs in transposon sequences, regions of repeated DNA sequences and in the coding region of genes.
DNA methylation patterns are heritable
Once a gene has been methylated, all the daughter cells from that cell retain the methylation, making it a heritable change. Changes made to DNA are perpetuated every time the cell divides: eventually, many cells carrying the modification will exist. Age and environmental factors can change the amount of DNA methylation that occurs during a lifetime. Inappropriate methylation of genes is implicated in diseases such as cancer and atherosclerosis (hardening of the arteries). Some genetic conditions are caused by inappropriate over or under methylation of the same region of DNA, such as Prader-Willi and Angelman syndromes.
Although most methylation is thought to be 'reset' when sperm and eggs are formed by meiosis, there is evidence that the methylation pattern of some genes can be inherited by offspring. This is causing a stir in biology, because it suggests that environmental stresses such as smoking or malnutrition experienced in a lifetime can have health impacts on that person's descendants for several generations.
The link between DNA methylation and cancer
Cancer is now recognised as both a genetic and epigenetic disease. While some types of cancers can be inherited, other cancers result from changes to DNA that accumulate throughout life. Whether inherited or spontaneous, cancer is caused by a change within a gene or series of genes, resulting in uncontrolled cell growth and multiplication.
Only a small number of the roughly 20,000 to 25,000 genes in humans are associated with cancer. There are three types of cancer-causing genes: oncogenes, tumour suppressor genes and DNA repair genes. Increasing evidence suggests that abnormal methylation of tumour suppressor genes, which causes a loss of normal function, plays a pivotal role in the development of many cancers.
The DNA in cancer cells often has a methylation pattern radically different to that found in normal cells. The promoter regions of genes in healthy cells are normally free of methylation, while the rest of the genome is heavily methylated. The reverse is true in most cancer cells, where the promoter regions are heavily methylated and entire regions of the genome can be abnormally suppressed or inactive.
DNA methylation, diet and the environment
Because DNA methylation can be affected by diet, stress and other environmental factors including heavy metals, pesticides, diesel exhaust and tobacco smoke it is one mechanism to explain how many dietary and environmental risk factors contribute to the development of cancer.
To maintain normal DNA methylation patterns, several essential nutrients are required from the diet, including a source of methyl groups (eg, methionine or choline) and folate. Folate found in green vegetables, legumes, oranges, and fortified juice and cereals has attracted attention because a diet low in folate is thought to increase the risk of developing colorectal cancer.
Phytochemicals are also being studied in mice and laboratory-grown cancer cells for their affect on DNA methylation. Genistein, one of the main phytochemicals in soy products, reactivates genes silenced by methylation and slows the growth of cancer cells. This is one mechanism proposed to explain why death rates from prostate cancer are low in men from countries with soy-rich diets, such as Japan.
Age related cancers
DNA methylation is a dynamic process, with the enzymes involved constantly working to methylate and demethylate CpG sites throughout the genome. These processes aren't perfect, and over time mistakes in DNA methylation can start to accumulate. Inappropriate methylation patterns can lead to inactivation of genes that should be expressed, which poses a particular problem when those genes are tumour suppressor genes vital for controlling normal cell growth. Age-related methylation is now thought to be one of the reasons cancer risk increases with the passing of the years.
The Human Epigenome Project
Research into epigenetics has already provided new and exciting advances in plant technology (Box 2: RNA interference and plant technology), potential cancer treatments and new tools for researchers trying to identify the function of genes. In recognition of the importance of DNA methylation in epigenetics, it is now the subject of the multi-million dollar Human Epigenome Project (Box 3: The Human Epigenome Project).
Posted September 2006.