Epigenetics – beyond genesRecent developments in epigenetics suggest that you may inherit more than genes from your parents.
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Key textInside 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 CpG's 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 CpG's 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). Related Nova topics: Biology meets industry – genomics, proteomics, phenomics More food, cleaner food – gene technology and plants The Human Genome Project – discovering the human blueprint
Box 1: RNA interference and epigeneticsRNA interference is a natural defence mechanism to control levels of gene activity where small segments of RNA cause messenger RNA to be degraded before it is translated into protein.RNA as a regulator of gene activity The discovery of RNA interference began in plants, when researchers tried to engineer petunia plants to produce more coloured pigment in flowers, by adding extra copies of a gene responsible for pigment formation. Instead of an increased amount of pigment, they found that many of the flowers lacked pigment. The extra copies of the gene were somehow suppressing the activity of the original gene. Later, researchers discovered that small RNAs were present in suppressed plants, that were absent in non-silenced plants. Continued research revealed an entirely new way of regulating gene activity that involved small RNAs. Types of small RNAs Small segments of RNA generally come in two varieties: small interfering RNAs from invading viruses and microRNAs that are encoded by genes in the cell. As research continues, new types of small interfering RNAs are being identified, particularly in plants. Small interfering RNAs Unlike DNA, RNA normally exists only in the single-stranded form in a cell. Because the genetic material of some viruses is made from double-stranded RNA, cells treat the presence of double stranded RNA as a sign of infection by a virus. When double-stranded RNA is found in the cell, it is chopped into short sequences of between 21 to 24 bases in length, and is then used as a guide to find and destroy single-stranded messenger RNA with the same sequence of bases. This mechanism helps prevent the invading virus from using the cell’s machinery to reproduce. Researchers can ‘trick’ the cell into destroying the messenger RNA from one of its own genes by deliberately introducing double-stranded RNA with the same nucleotide sequence as a gene to be silenced. Because the messenger RNA is destroyed before it can be translated into a protein, the normal appearance or function of the cell is changed. Small interfering RNAs and methylation of DNA in plants In plants, small interfering RNAs can also trigger the methylation of DNA. Small RNAs that are similar in sequence to a region of DNA, cause the DNA to be methylated. The details of the mechanism are not yet fully understood, but it represents yet another way to control the level of gene activity. MicroRNAs Thousands of microRNAs have been identified in many species, including humans, but their role in the cell was a mystery until recently. MicroRNAs are regulators of embryo development, cell replication, plant development and stress responses. Because they are involved in timing of cell development and metabolism, any change to them can trigger cancer. Researchers have discovered that cancer cells contain less microRNA than healthy cells, and each type of cancer has its own distinctive microRNA fingerprint. MicroRNAs are also known to regulate the expression of c-Myc, an oncogene that is implicated in 15 per cent of human cancers. The discovery of microRNA and its role in development has led to a new appreciation of parts of the genome that were once considered ‘junk DNA’. Related sites
Box 2: RNA interference and plant technologyHairpin RNA interference (RNAi) is a gene silencing technology developed by CSIRO that is used to develop new plant traits. It makes use of the ability of RNA to fold back on itself to form a ‘hairpin’ shaped piece of double stranded RNA. The hairpin RNAi triggers the cell’s RNA interference mechanisms to degrade messenger RNA from the target gene, reducing or completely silencing its expression.Hairpin RNAi has been used to create plants such as the blue rose, virus-resistant wheat and barley, and cottonseed that makes healthy food oils. Hey true blue While roses have long been available in a wide range of colours, the holy grail of rose breeders, the blue rose, has proved impossible to achieve using standard plant breeding methods. Victoria-based company Florigene Pty Ltd have used hairpin RNAi to create the world’s first true blue rose. These roses have their natural pigment removed by hairpin RNAi, and genes from the pansy and the iris added to allow them to make a blue pigment instead. Virus resistant wheat and barley Hairpin RNAi has been used to develop varieties of wheat and barley that are immune to yellow dwarf virus. By targeting segments of viral genes with RNAi, the transgenic cereal plants are made immune to this costly disease. Healthier cottonseed oil Cottonseed oil is used to make cooking oils and margarines, but the process used to treat the oil to prolong shelf life and make it suitable for cooking creates unhealthy trans fats, which raise blood cholesterol levels. Using harpin RNAi, CSIRO has developed a cottonseed oil that is high in oleic acid, which makes it suitable for cooking purposes without the need for treatment. Genetic research RNA interference is providing scientists with new tools to study the function of genes. By observing the effect of ‘knocking down’ (reducing) or ‘knocking out’ (eliminating) the amount of a protein, researchers can deduce its normal function in the cell. RNA interference offers advantages over the traditional method of inducing mutations to silence genes, because it can be used to reduce, rather than completely eliminate, gene function. This allows researchers to study the function of gene products whose complete absence results in the death or severe malfunction of the cell. Related sites
Box 3: The Human Epigenome ProjectFollowing the Human Genome Project, which was completed in 2003, the latest addition to the big human biology research efforts is the Human Epigenome Project (HEP), run by the Human Epigenome Consortium. The project aims to identify, catalogue and interpret the DNA methylation patterns of all human genes in all major tissues.The Human Epigenome Consortium began with a pilot study in 2003 into the methylation patterns of a region of chromosome 6. This region carries genes crucial to the human immune system that have been implicated in many diseases, particularly autoimmune diseases such as diabetes and rheumatoid arthritis. The study examined about 0.4 per cent of the genes in the human genome, identifying CpG positions that are variably methylated and involved in modifying gene activity. The study also developed automated methods to rapidly and accurately identify methylation patterns in a genome, simplifying the analysis of larger sections of the human epigenome. In June 2006, the project released DNA methylation profiles of chromosomes 6, 20 and 22 for 12 different tissue types. The data accumulated by the project is publicly available for use in non-commercial research efforts. Related sites
Activities
Further readingAustralasian Science November/December 2007, pages 16-18 Jewels among the junk (by Ken Pang) Investigates the link between ‘junk DNA’ and medical disorders.
November/December 2007, page 12 Epigenetic nanosensors to test for breast cancer Reports on the development of nanoscale biosensors to improve early detection of breast cancer.
March 2007, pages 25-27 How cancer cells take control (by Susan Clark and Branwen Morgan) Explains how cancer is about more than what’s in our genes.
Environmental Health Perspectives March 2006 Epigenetics: The science of change Provides a technical review of research on epigenetics, including diagrams.
Nature 7 August 2008, pages 795-798 Epigenomics: Detailed analysis (by Laura Bonetta) Discusses research tools and applications of the epigenome for treating disease.
New Scientist 11 February 2009, page 12 Gene caps may turn viruses cancerous (by Bob Holmes) Looks at epigenetic modification of viral genes and their association with cancerous cells.
29 November 2008, page 12 Memories may be stored on your DNA (by Devin Powell) Claims that methyl groups on DNA may help form memories.
12 July 2008, pages 28-33 Rewriting Darwin: The new non-genetic inheritance (by Emma Young) Outlines inheritance of characteristics acquired by parents through epigenetics.
28 June 2008, pages 44-47 MicroRNAs: The cell's little emperors (by Henry Nicholls) Describes the role of microRNAs in gene expression and their use in treatment for diseases.
13 June 2007, page 20 ‘Junk’ DNA makes compulsive reading (by Andy Coghlan) Explores the role of extra DNA fragments.
19 May 2007, page 8 New gene therapy targets cholesterol (by Linda Geddes) Explores a new technique to cut cholesterol levels
7 April 2007, pages 42-45 Turn genes on, turn diseases off (by Bob Holmes) Looks at the possibilities of using RNA interference based treatments for all kinds of diseases.
13 November 2006 You are what your grandmother ate (by Roxanne Khamsi) A new mouse study shows that a mother's diet can change gene behaviour for at least two generations.
24 May 2006 Safety scare over 'the new gene therapy' (by Peter Aldhous) Reports on an experiment using RNAi that caused liver damage in mice.
1 April 2006, page 17 Single RNA jab adjusts blood cholesterol (by Andy Coghlan) Describes how an injection of RNAi molecules can block the gene that makes ‘bad’ cholesterol.
4 March 2006, page 15 Have we got cell division all wrong? (by Rowan Hooper) Describes a new insight into the separation of chromosomes during mitosis.
6 January 2006, page 10 Men inherit hidden cost of dad's vices (by Rowan Hooper) Describes how poor nutrition and smoking in early life may influence the health of men's sons and grandsons.
17 November 2005 The food you eat may change your genes for life (by Alison Motluk) Suggests that swallowing a pill or eating a specific food supplement may permanently change the expression of your genes.
5 September 2005 Human stem cells become unstable in the lab (by Gaia Vince) Looks at the effect of culturing stem cells for long periods in the lab on genes known to cause cancer.
2 August 2005 Famine increases the risk of schizophrenia (by Gaia Vince) Reports on a study in China showing an increased risk of schizophrenia for babies born during famine.
11 June 2005, page 7 Toxic effects can pass down the generations (by Rowan Hooper) Suggests that epigenetic changes are responsible for decreases in sperm counts for at least four subsequent generations of male rats exposed to pesticides.
8 June 2005 New suspect implicated in the development of cancer (by Andy Coghlan) Reports on three studies suggesting that microRNA misregulation can cause cancer.
31 May 2005 Embryonic stem cells pass key safety test (by Shaoni Bhattacharya) Suggests that the methylation patterns of six genes in four embryonic stem cell lines does not change when grown in the lab.
11 April 2005 Pregnant smokers increases grandkids' asthma risk (by Gaia Vince) Suggests that the effects of smoking when pregnant can be passed on to children and grandchildren.
27 November 2004, page 36-39 Unlocking the secret power of RNA (by Philip Cohen) Reports on the growing awareness of a more important role for RNA in the cell.
10 November 2004 Unlikely ally rescues gene-blocking therapy (by Philip Cohen) Suggests that cholesterol can be used to enhance the effect of injecting RNAi molecules to treat diseases in humans.
30 October 2004, page 47 Life sentence (by Alison Motluk) Reports on diet during pregnancy and the increased risk of heart disease and diabetes in children.
15 September 2004 Gene technique to fight human blindness (by Peter Farley) Reports on the first human trial of RNAi to treat a condition that causes blindness.
Scientific American 14 March 2007 How to make – or break – memory (by Nikhil Swaminathan) Reports on a study that memories may be formed by the same gene-silencing tool that is used in embryonic development.
12 February 2007 Ask the experts Answers the question ‘What is junk DNA, and what is it worth?’
5 July 2005 Identical twins exhibit differences in gene expression (by Sarah Graham) Suggests that the differences observed between identical twins may be due to different DNA methylation patterns.
1 October 2004, pages 30-37 The hidden genetic program of complex organisms (by John Mattick) Describes the regulation of genes by RNA encoded in ‘junk DNA’ and its role in development and evolution.
1 October 2004, pages 68-71 Hitting the genetic off switch (by Gary Stix) Reports on companies considering the use of drugs and RNAi in therapies to block the action of RNA.
1 December 2003, pages 78-85 The unseen genome: Beyond DNA (by W. Wayt Gibbs) Reviews the epigenetic control of gene expression by DNA imprinting and methylation.
1 November 2003, pages 26-33 The unseen genome: Gems among the junk (by W. Wayt Gibbs) Reviews the role of RNA encoded in the ‘junk DNA’ and the role of RNA in control of gene expression.
August 2003, pages 26-33 Censors of the genome (by Nelson Lau and David Bartel) Provides an overview of the RNAi mechanism in plant and animal cells.
Velocity – science in motion June 2008 Honeybees throw light on diet and gene expression Describes diet-induced epigenetics in bees.
Useful sitesInheritance... more than just genes information sheet (CSIRO, Australia)
Provides information about epigenetics, or non-gene factors, that affect traits in plants.
Australian Broadcasting Corporation
Epigenetics (The Science Show, 7 February 2009, Australian Broadcasting Corporation)
Transcript of an interview discussing epigenetics in general, as well as research into yeast and human epigenetics.
Centre for Genetics Education, Australia
Basic principles of genetics: An introduction to Mendelian genetics (Palomar Community College, USA)
Provides information on genetics including the probability of inheritance and exceptions to simple inheritance.
Rediscovering biology: Molecular to global perspectives (Learner.org, USA)
National Cancer Institute (USA) A series of tutorials that use graphics and simple text to provide information about cancer.
Inside cancer: Multimedia guide to cancer biology (Cold Spring Harbour Laboratory, USA)
Uses animations to describe aspects of cancer. Includes the sections ‘Hallmarks of cancer’, ‘Causes and prevention’, ‘Diagnosis and treatment and ‘Pathways to cancer’.
Epigenetics: A web tour (Science magazine, USA)
A collection of articles and web resources on epigenetics, including DNA methylation, RNA interference and histone modification.
Glossarybase (in DNA). Any one of four nitrogen-containing bases (adenine, thymine, guanine and cytosine). The sequence of the bases in DNA determines the sequence of amino acids in all proteins found in living things.base pairs. Two bases held together by weak chemical bonds. The double helix shape of DNA is dependent on its two strands being held together by the bonds between the base pairs. In DNA, the bases that pair are adenine with thymine and guanine with cytosine. chromosome. A long DNA molecule that contains the genes of the organism. Chromosomes are visible in cells during cell division. DNA (deoxyribonucleic acid). The nucleic acid forming the genetic material of all organisms, with the exception of some viruses which have RNA. DNA is present in the nucleus and other organelles such as mitochondria and chloroplasts. DNA repair genes. Encode proteins that correct mistakes in DNA caused by incorrect copying during replication and environmental factors such as by-products of metabolism, exposure to ultraviolet light or mutagens. The DNA repair process must operate constantly to correct any damage to the DNA as soon as it occurs. For more information about the role of DNA repair genes in cancer see Genetics of cancer (Learner.org, USA). enzyme. A protein that acts as a catalyst. Every chemical reaction in living organisms is facilitated by an enzyme. epigenetics. Is the study of heritable changes in gene activity that occur without a change in the sequence of the genetic material. Epigenetics literally means ‘in addition to genetics’. gene. The basic unit of inheritance. A gene is a segment of DNA that specifies the structure of a protein or an RNA molecule. genetic conditions. Those conditions or diseases that result from abnormalities in chromosomes or DNA, and are inherited. genome. The total genetic material of an individual or species. histones. Proteins found associated with DNA in eukaryotic cells that play a role in gene regulation. The DNA winds around the histone protein to form chromatin. For more information about the role of histones see The nucleus (Kimball’s Biology Pages, USA). messenger RNA. RNA molecule that is transcribed from DNA and is used to direct the synthesis of a protein. meiosis. A division of the nucleus that involves the separation of pairs of chromosomes into different cells. Meiosis takes place in the reproductive organs of sexually reproducing organisms. Meiosis involves two nuclear divisions, both of which may take place before division of the cell itself is complete. The eventual result is four cells, each with half the number of chromosomes present in the original cell. Crossing over of chromosomes during meiosis creates new combinations of genes in the progeny that were not present in either adult. For more information see How cells divide: Mitosis versus meiosis (Public Broadcasting Service, USA). mutation. A change in the DNA sequence of a gene that may be harmful or beneficial. It is the only process that actually leads to new forms of a gene, and it is the ultimate source of all variation. oncogenes. Mutated forms of genes which produce protein products that normally enhance cell division or inhibit normal cell death. For more information see Genetics of cancer (Learner.org, USA). promoter. The DNA sequence adjacent to the coding sequence of a gene, which interacts with inducers or repressors and RNA polymerase to determine whether that gene is active or not. protein. A large molecule composed of a linear sequence of amino acids. This linear sequence is a protein's primary structure. Short sequences within the protein molecule can interact to form regular folds (eg, alpha helix and beta pleated sheet) called the secondary structure. Further folding from interaction between sites in the secondary structure forms the tertiary structure of the protein. Proteins are essential to the structure and function of cells. They account for more than 50 per cent of the dry weight of most cells, and are involved in most cell processes. Examples of proteins include enzymes, collagen in tendons and ligaments and some hormones. For more information see Protein structure and diversity (Molecular Biology Notebook, Rothamsted Research, UK). RNA (ribonucleic acid). A nucleic acid similar to DNA. There are a number of types of RNA, the major ones being messenger RNA, transfer RNA and ribosomal RNA. RNA can serve as a messenger between DNA and proteins, as a structural molecule, as an enzyme and as regulators of gene expression. In some viruses RNA is the genetic material. For more information see Introduction to RNA and its functions (University of Newfoundland, Canada). tumour suppressor gene. Genes that encode proteins that normally repress cell division or enhance cell death. For more information see Genetics of cancer (Learner.org, USA).
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