In the beginning of the twentieth century, developmental biology and genetics were two separate disciplines. The word epigenetics was coined by Waddington to link the two fields. Epigenetics literally means “on top of or in addition to genetics.” It is defined as the study of mechanisms or pathways that initiate and maintain heritable patterns of gene expression and gene function without changing the DNA sequence.
Many human diseases are caused in whole or in part by environmental factors. It has been accepted that environmental chemicals can cause many of these diseases through changes in the genome (i.e., genetic effects). However, environmental chemicals can also cause effects in a variety of other ways. The study of these enduring changes, where life meets the genome, is epigenetics. Epigenetic discoveries have a great impact upon the understanding of child development, mental health, and how public health and well-being can be maintained in a changing world.
What id Epigenetic?
The term epigenetics refers to heritable changes in gene expression (active versus inactive genes) that does not involve changes to the underlying DNA sequence; a change in phenotype without a change in genotype. Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state. Epigenetic modifications can manifest as commonly as the manner in which cells terminally differentiate to end up as skin cells, liver cells, brain cells, etc. Or, epigenetic change can have more damaging effects that can result in diseases like cancer.
In other words, Epigenetics refers to the addition or deletion of a methyl group to a DNA base, turning the gene on or off, or to packaging of the chromatin structure by silencing or opening regions of the genome by winding or unwinding the DNA around histones.
Epigenetic and developmental epigenetic changes happen in all humans as part of normal growth, development, and aging. Some of the changes can alter the risk of developing certain diseases.
At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change. Numerous researches are continuously uncovering the role of epigenetics in a variety of human disorders and fatal diseases.
- DNA Methylation – DNA methylation is a chemical process that adds methyl group to DNA. This prevents certain genes from being expressed. Methylation can be transient and can change rapidly during the life span of a cell or organism, or it can be essentially permanent once set early in the development of the embryo.
- Histone Modification – Histones are proteins that are the primary components of chromatin, which is the complex of DNA and proteins that makes up chromosomes. Histones act as a spool around which DNA can wind. When histones are modified after they are translated into protein (i.e., post-translation modification), they can influence how chromatin is arranged, which, in turn, can determine whether the associated chromosomal DNA will be transcribed. There are two main ways histones can be modified: acetylation and methylation. Acetylation is usually associated with active chromatin, while deacetylation is generally associated with heterochromatin. On the other hand, histone methylation can be a marker for both active and inactive regions of chromatin.
- RNA-Associated Silencing – Genes can also be turned off by RNA when it is in the form of antisense transcripts, non-coding RNAs, or RNA interference. RNA might affect gene expression by causing heterochromatin to form, or by triggering histone modifications and DNA methylation.
Causes of Epigenetic Changes
Interactions with the environment can cause epigenetic changes that affect how the genes work. These interactions include behaviors like smoking, eating, drinking, exercise, and exposure to natural and manufactured chemicals in air, water, and food.
Environmental Factors – Environmental factors are one cause. These can include, but are not limited to –
- Exercise
- Diet
- High-fat diet – Studies show that pregnant mothers’ high-fat diets to epigenetic changes and later development of tumors in their offspring.
- Lack of essential vitamins and nutrients, such as choline, B vitamins, and folic acid. An NICHD-supported animal study linked lack of B vitamins and folate in pregnant mothers’ diets with epigenetic changes, obesity, and heart disease in their offspring.
- Intake of resveratrol – This substance, found in red grapes and red wine, may help protect against cancer.
- Nicotine, the drug that makes cigarettes addictive
- Alcohol
- Chemicals in the living space or workplace – Asbestos, a toxic chemical that is sometimes found in older buildings. Bisphenol A (BPA), a chemical in many plastic containers, such as water bottles.
- Heavy metals (e.g., cadmium) can disrupt DNA methylation.
- Vinclozolin, a widely used pesticide, can alter DNA methylation in exposed laboratory animals. These changes persist in unexposed offspring through several generations.
- Deficiencies in folate and methionine, both of which are involved in cellular processes that supply methyl groups needed for DNA methylation, can change the expression (imprinting) of growth factor genes
- Medications
These environmental factors are only a few examples of things that can cause epigenetic changes. Many other environmental factors, known and unknown, can cause epigenetic changes.
Some epigenetic changes appear to happen on their own, without any clear cause.
Some epigenetic changes happen as a result of certain types of chemical reactions in the body. Even some genes contribute to epigenetic changes.
Cesarean Delivery May Cause Epigenetic Changes In Babies DNA – Babies coming into the world by cesarean section experience epigenetic changes, a study has found. So far there has not been enough follow up to know whether the effects are long lasting, but the discovery may explain the relatively poorer outcomes for babies delivered in this way. Cesarean delivery, where the mother’s abdomen and uterus are surgically cut open to remove the baby, was once a last, desperate option. Studies found higher rates of methylation in stem cells from babies delivered by cesarean than via vaginal birth. Methylation of DNA affects whether genes are expressed or not within a cell and is the major path through which environmental factors can alter the expression of genetic traits.
Epigenetic Inheritance – It may be possible to pass down epigenetic changes to future generations if the changes occur in sperm or egg cells. Most epigenetic changes that occur in sperm and egg cells get erased when the two combine to form a fertilized egg, in a process called “reprogramming.” This reprogramming allows the cells of the fetus to “start from scratch” and make their own epigenetic changes. But scientists think some of the epigenetic changes in parents’ sperm and egg cells may avoid the reprogramming process, and make it through to the next generation. If this is true, things like the food a person eats before they conceive could affect their future child. However, this has not been proven in people.
Epigenetics and Diseases
Alterations in epigenetic pathways have been shown to be implicated in common human diseases
Common, chronic diseases of Western societies, such as eczema, asthma, diabetes, coronary heart disease, depression and cancers, are very different. They are nearly all multifactorial, so defining the cause is impossible. There are many contributing factors, including the person’s genetic makeup. Imagine driving along a narrow, winding country lane in the rain, having just had a row with your partner. The windscreen is fogged up, and your car has rather bald tyres. You round the corner to find the lane blocked by a tractor backing into a field, and crash into the tractor. . A few examples are given below to illustrate the importance of epigenetic pathways in disease development.
- Epigenetic and Cancer – The first human disease to be linked to epigenetics was cancer, in 1983. Epigenetic changes have been observed in virtually every step of tumor development and progression. Too little DNA methylation (hypomethylation) is believed to initiate chromosome instability and activate oncogenes.
A malignant cell can have 20- 60% less genomic methylation than its normal counterpart. Conversely, too much DNA methylation (hypermethylation) may initiate the silencing of tumor suppressor genes. Medical researchers are evaluating epigenetic markers as a means for early cancer diagnosis and prediction of clinical outcome. Therapeutics based on epigenetic strategies are also being considered for cancer treatment and prevention. How epigenetic changes may be a mechanism of environmental chemical-induced cancers is being researched as well.
- Epigenetics and Aging – DNA methylation decreases as cells age. Identical twins are epigenetically indistinguishable early in life, but have substantial differences in epigenetic markers with age. This observation suggests an important role by the environment in shaping the epigenome. It has been shown that the process of aging involves some epigenetic pathways that have been identified in the process of carcinogenesis.
- Epigenitics and Mental Retardation – Fragile X syndrome is the most frequently inherited mental disability, particularly in males. Both sexes can be affected by this condition, but because males only have one X chromosome, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and “autistic-like” behavior. The syndrome is caused by an abnormality in the FMR1- fragile X mental retardation 1 gene. People who do not have fragile X syndrome have 6 to 50 repeats of the trinucleotide CGG in their FMR1 gene. Loss of this specific protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMR1 methylation is the real syndrome culprit.
- Other human diseases – There is increasing evidence that epigenetic changes play a
critical role in the development of certain human diseases, such as, neurodevelopmental
disorders, cardiovascular diseases, type-2 diabetes, obesity and infertility.
Epigenetic Therapy
The use of drugs to correct epigenetic defects, is a new and rapidly developing area of pharmacology. Epigenetic therapy is a potentially very useful form of therapy because epigenetic defects, when compared to genetic defects, are thought to be more easily reversible with pharmacological intervention. In addition to holding promise as therapeutic agents, epigenetic drugs may also be able to prevent disease. However, epigenetic therapy has its limitations, such as the fact that both DNMT as well as HDAC inhibitors may activate oncogenes due to lack of specificity, resulting in accelerated tumor progression. The drugs include –
DNMT inhibitors (DNA demethylating drugs) – These drugs inhibit methylation of DNA by inhibiting the DNMTs. Most of the DNMT inhibitors presently available are not specific for any of the DNMTs. Inhibition of DNA methylation can be therapeutically useful in cancer where hypermethylation of promoter regions of genes is the most well established epigenetic change known to occur. DNMT inhibitors are also being investigated as a means to reactivate the methylated and silenced foetal haemoglobin gene in patients with thalassaemia and sickle cell anaemia in order to increase production of haemoglobin F, thereby helping in the correction of anaemia that characterizes these diseases. Some of these drugs such as zebularine and procaine are small molecule DNMT inhibitors.
Non-nucleoside analogue DNMT inhibitors – The myelotoxic effects of the nucleoside analogue inhibitors has encouraged the search for inhibitors of DNA methylation that are not incorporated into DNA because of structural differences from cytosine. These non-nucleoside analogue inhibitors are undergoing preclinical trials. Some of these drugs such as procainamide and procaine have the potential advantage as these have already been extensively used in clinical practice.
Antisense oligonucleotides – Antisense oligonucleotides are short, defined sequences of nucleotides that are complementary to mRNAs and hybridize with them and make them inactive, thereby blocking translation.
HDAC inhibitors (chromatin remodelling drugs) – These drugs inhibit HDACs, which along with HATs, help maintain the acetylation status of histones. The anticancer effects of these drugs are thought to be due to the accumulation of acetylated histones leading to the modulation of the transcription of specific genes whose expression causes inhibition of cancer cell growth. Some HDAC inhibitors such as suberoylanilide hydroxamic acid and depsipeptide have been undergoing. Some HDAC inhibitors such as suberoylanilide hydroxamic acid37 and depsipeptide38 have been undergoing.
Reference
http://www.nature.com/scitable/content/epigenetic-diseases-and-their-causes-and-symptoms-37397
http://science.howstuffworks.com/life/genetic/epigenetics2.htm
https://www.nichd.nih.gov/health/topics/epigenetics/conditioninfo/pages/risk.aspx
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780862/
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http://www.zymoresearch.com/learning-center/epigenetics/epigenetic-biomarkers-treatments
http://science.howstuffworks.com/life/genetic/epigenetics4.htm
http://onlinelibrary.wiley.com/doi/10.1002/047001153X.g103227/pdf