This month, we are fortunate to have a paper describing the subject written by a nutritional science student studying dietetics.
References are at the end.
The term epigenetics refers to heritable traits that do not involve changes to the underlying deoxyribonucleic acid (DNA) sequence. The prefix epi- in ‘epigenetics’ means "on top of" or "in addition to", so ‘epigenetic’ traits exist on top of or in addition to the traditional molecular basis for inheritance. Post-synthetic modifications of either the DNA or proteins closely connected with the workings of DNA are key factors in the epigenetic process. The term ‘epigenome’, stemming from ‘genome’, refers to the epigenetic state of a cell.
Most of the epigenome is established during embryonic and fetal development. However, some epigenetic changes do take place in later development. Some Hox developmental genes are methylated after birth, as is at least one gene controlling adult behavior. External influences on proteins involved in the epigenetic processes can be seen with long-term diseases like cancer.
DNA methylation is a chemical modification of DNA which involves the addition of a methyl group to a nucleotide sequence. Because this modification can be inherited and then later removed without making a change to the original DNA sequence, methylation is considered part of the epigenetic code and a highly important epigenetic mechanism. Methylation is also an essential element of normal development. Under typical circumstances, DNA methylation is made use of as a means of genome control, sequestering the DNA and making it less available for transcription.
In adult tissues, DNA methylation typically occurs in a CpG dinucleotide context (cytosine and guanine nucleotides linked together by a phosphate). CpG islands are areas of the DNA with high concentrations of unmethylated CpG sites. Most CpG islands are associated with genes. In the rare cases when CpG islands do become methylated, extended, sometimes permanent shutdown of the associated gene occurs.
DNA methylation may affect the transcription of genes in two ways. First, the actual methylation of the DNA may hamper the binding of transcriptional proteins to the gene. Secondly, methylated DNA can be bound by methyl-CpG- binding domain proteins. These proteins then recruit other chromatin remodeling proteins that can modify histones, forming compact, inactive chromatin, called ‘silent chromatin’.
Chromatin is the structure of proteins (histones) and DNA, wound tightly into the cell nucleus. Certain substances such as acetyl groups, enzymes, and some forms of ribonucleic acid (RNA) can modify chromatin structure to create changes in gene expression. One such effect of chromatin modification is called imprinting. Imprinting is when one of the two alleles from a standard gene pair is silenced through an epigenetic process. The expression of imprinted genes is species, tissue and developmental stage dependent and may play an important role in the speciation of mammals. In mice and humans, approximately 80 imprinted genes have been identified.
Imprinted genes function as though they have a single set of chromosomes, expressing either the maternally or paternally inherited allele, based on where they were inherited from. Because of this genetic ‘memory’, mutations of these genes can have severe health related consequences, the results being diseases such as cancer and certain pediatric developmental disorders. Prader–Willi syndrome and Angelman syndrome are congenital imprinting disorders. Both are caused by errors to the same part of chromosome 15. Errors inherited from the father result in Prader–Willi syndrome, those inherited from the mother result in Angelman syndrome. Links have been made with Autism to the same region on chromosome 15.
Metastable epialleles are alternate forms of genes that undergo epigenetic modifications related to maternal nutrition and environmental exposure during very early development. The fetus is quite vulnerable to environmentally-induced epigenetic changes early on in development. It has been found that simple dietary changes can protect against the negative effects of environmental toxins on the fetal epigenome. Epigenetic effects are not solely prenatal events, but occur over the full course of a human life span. Postnatal exposure to nutritional, chemical and physical elements in the environment can alter the epigenome.
There is evidence linking a wide variety of illnesses, behaviors, and other health problems with epigenetic alterations, including almost all types of cancer, cognitive dysfunction, respiratory, cardiovascular, reproductive, autoimmune, and neurobehavioral illnesses. Postnatal epigenetic states are susceptible to being modified by environmental factors as well. Known or suspected contributors to the epigenetic development of abnormal phenotypes includes heavy metals, pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria, and basic nutrients (or rather, the lack thereof).
During aging, an epigenetic drift occurs throughout the body systems. The hypermethylation of rDNA repeats with age, and can lead to a decrease in transcription of many genes. Genetically and environmentally triggered epigenetic alterations occur day after day, while age, diet, and disease related deteriorations interact with other processes. As these accumulate, the occurrence of age-related disease increases.
In the past, it was generally assumed that starting the development of an embryo, its genetic slate was “wiped clean”, a concept relating well to the totipotency of the zygote. Transgenerational epigenetic effects come about because of incompletely erased epigenetic marks, caused by the experiences and exposures of previous generations. In various places across the genome, epigenetic changes seem to resist being wiped away more than the rest. These “incomplete erasures” result in patterns of inheritance from one generation to the next.
A survey was done of more than 5000 fathers who had children in the early 1990’s. All these men were or had been smokers. Of these men, 166 started smoking before they were 11, during a prepubescent time when the body is especially sensitive to environmental stress. The data was checked for the influence of factors such as socio-economic status, and whether the fathers had continued smoking until their child was conceived. The men who started smoking before puberty had sons who, at age nine, were much fatter than the average. No correlating effect was seen for daughters.
Research looking at historical records in Sweden, traced families back three generations and assessed their dietary habits based off harvest records. People whose grandparents experienced slight famine around the ages of 9 to 12 years old seemed to live longer. The grandchildren of people who had plenty of food around that age tended to be at higher risk for diabetes and cardiovascular disease. Also, the diet of grandfathers was only found to be linked to the lifespan of grandsons, and the grandmothers only affected their granddaughters. The nutrition of the grandmother during pregnancy not only influences the mother’s nutrition during the gestation period, but also affects the grandchild’s birth weight.
Effects from exposure to chemical toxins may carry on four generations or more. Pregnant rats were exposed to the fungicide (and endocrine disrupter) Vinclozolin. The male young had increased sperm cell apoptosis, decreased sperm number and decreased sperm motility. These alterations were passed on to male offspring for 4 generations through the male line, despite no further treatment with Vinclozolin.
The epigenetic process includes a mechanism by which dietary components can influence genes’ ability to produce enzymes and other proteins that may control major metabolic processes in the body. This same mechanism is also a main component in the process of cell differentiation during embryonic development. Lipids and lipoprotein components interact directly with chromatin structure to influence gene expression. So the intake of specific dietary fatty acids during establishment of epigenetic mechanisms could cause permanent changes in gene expression. Epigenetic changes that occur during early life may be capable of influencing susceptibility to chronic diseases in adulthood.
Different people may respond very differently to certain dietary variations. There is a lot of room for gene-diet interaction because of the high amounts of enzymes, transport proteins, receptors and transcription factors involved in the absorption and metabolism of dietary fat. People of a specific genotype called apo E4 usually have higher low-density lipoprotein (LDL) levels, are at higher risk for cardiovascular disease, and respond better to a low-fat diet. While moderate alcohol consumption can have protective effects in cardiovascular disease, this protection is greatest in people with slower alcohol metabolism, stemming from a variant form of the alcohol dehydrogenase enzyme. Methyltetrahydrofolate reductase (MTHFR) is an enzyme involved in folic acid and homocysteine metabolism. A common polymorphism that occurs is the replacement of the cytosine by thymine at a specific based pair. If both cytosines are replaced by thymine in a person’s MTHFR gene, their homocysteine levels more than double when on a low-folate diet, which raises their risk for cardiovascular disease.
Folate, methionine, zinc and vitamin B12 affect the activity of enzymes that supply methyl groups for different cellular methylation processes. Varying levels of these micronutrients can influence the rate of disease manifestation, as is seen in certain cancers. Reduced folate levels are connected to neural tube defects when occurring during gestation, along with genomic instability and hypomethylation. Methyl-deficiency in the diet has also been shown to induce liver cancer.
The major polyphenol from green tea, Epigallocatechin gallate (better known simply as ‘EGCG’) is a target of invitro methylation and an inhibitor of nuclear DNA methytransferase activity, along with reducing the growth of cancer cells. When used in the treatment of cancer cell lines, the hypomethylation and transcriptional activity of previously hypermethylated genes occurred. Many other substances, such as baicalein and curcumin, histone deacetylase inhibitors, ibuprofen, lycopene, pomegranate extracts, quercetin, selenium, alpha and gamma-tocopherols, valproic acid, vitamin D, and zinc are known for their effect on epigenetic processes.
The coat color gene agouti gives some mice yellow color fur, as well as a predisposition to obesity, diabetes, and tumor development. When pregnant female brown mice are fed a diet supplemented with methyl groups, a larger percentage of their offspring are born without the effects of the agouti gene in comparison to those fed the standard diet. The methyl groups block proteins that approach the agouti gene, which otherwise would produce more proteins, thus setting the effects of the gene into motion. That methylation status affects both the phenotype of the animal and of its offspring is indication that some epigenetic modifications of the genome are not fully erased during oogenesis, and go on to influence the epigenetic state of the genome and the activity of genes in the next generation
Asthma is viewed as a theoretically preventable environmental disease. Epigenetic regulation could play a substantial part in the gene/environment interactions that can lead to asthma or modify the risk level of it. The transmission of this risk may develop over multiple generations as a result of epigenetic changes after environmental exposure, whether in early development or later in life.
In the realm of neuropsychological illnesses, the term ‘environmental’ encompasses the traditional physical parameters of infectious agents, pollutants and other influencing factors on the physical surroundings; along with drugs, injuries, nutritional deficiencies, and an individual’s psychosocial conditions. Psychosocial and/or physiological stressors can interact with genetic preconditioning, altering brain chemistry and thereby mental health.
On average, if one of a set of identical twins develops schizophrenia, the risk is less than 50% that the other twin will as well. This makes a strong case for the involvement of environmental influences. Similar outcomes are found in depression and bipolar disorder. Studies based on a famine in the Netherlands during World War II, and on the Chinese famine in the mid 1900’s produced evidence that maternal starvation during pregnancy can double the risk of schizophrenia among offspring. Nutritional deficiencies could produce epigenetic mutations in genes required for normal brain development. Folate deprivation could hinder DNA repair or make changes in DNA methylation.
The reelin protein helps regulate processes of neuronal migration and positioning in the developing brain. Later, reelin continues to do work in the adult brain. Reduced expression of reelin and its mRNA levels have been found in the hippocampus, cerebellum, basal ganglia, and cortex, and in the blood levels of schizophrenia sufferers, but in only the cortex of those with bipolar. Hypermethylation is thought to be the cause of the reduction in reelin levels. Studies have displayed evidence that prenatal exposure to a number of microbial infections, including those caused by rubella, toxoplasmosis, and influenza can raise the risk of schizophrenia. Fetuses having had this exposure in utero secrete significantly less reelin once born. The risk appears to be highest after an infection during the second trimester. The reelin pathway has also been considered as a link between Alzheimer’s disease and schizophrenia.
Cancers are not just genetic, but also epigenetic abnormalities. During carcinogenesis, the genome simultaneously undergoes genome wide hypomethylation and regional hypermethylation of CpG islands. Chromosomal instability, activation of oncogenes by demethylation, and the silencing of tumor suppressor genes by hypermethylation are all changes in cancer cells which can be caused from epigenetic changes. Methylation of CpG islands contributes to gene silencing. Methylation of the CpG island at the retinoic acid receptor causes a protein fusion known to induce leukemia in humans. The reelin gene is considered a tumor supporter, but the means by which it functions are varied. Expression has been found to be suppressed in pancreatic cancer, whereas in prostate cancer, reelin expression is excessive.
As we identify more and more epigenetically unstable locations in the human genome, screening for epigenetically susceptible diseases at an early age will be made possible, along with more accurate disease diagnosis. This knowledge will allow for more precise and effective monitoring of an individual’s health. Because epigenetic profiles are potentially reversible, preventions and therapies, such as nutritional supplementation and/or pharmaceutical treatments can be developed to help counteract and even reverse negative epigenetic alterations.
Studies have shown that many disorders, such as obesity, cardiovascular disease, diabetes, hypertension, asthma and schizophrenia, have roots in early nutrition and environmental exposure during gestation. The potential for epigenetic change continues from conception until the time of death. A person’s lifetime not only affects their own epigenome, permanently modifying things like appetite control, metabolic balance, and disease susceptibility, but that of the epigenome for generations to come as well.
- Brain Health: The Gluten (Dis)Connection
- Nutrition, genes, and brain dysfunctions: Folate
- Brain Health: Omega-3 Fatty Acids ("Fish Oil")
- Inflammation of Body and Brain
- Epigenetics and Human Health: Linking Hereditary, Environmental and Nutritional Aspects
- Feed Your Genes Right: Eat to Turn Off Disease-Causing Genes and Slow Down Aging
- Nutritional Genomics: Discovering the Path to Personalized NutritionFood Science Books)
- Our Toxic World: A Wake Up CallEnvironmental Science Books)
Buttriss, J. L. "Diet-gene interactions and current EU research: something for everybody!" Nutrition Bulletin 31 (2005): 65-68. Mar. 2006. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=23462978&site=ehost-live&scope=site
Charles, Schmidt W. "A Deeper Look into Mental Illness." Environmental Health Perspective 115 (2007): A404-410. Aug. 2007. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=26375828&site=ehost-live&scope=site
Cooney, Craig A. "Epigenetics - DNA based mirror of our environment?" Disease Markers 23 (2007): 121-37. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=24162570&site=ehost-live&scope=site
Dolinoy, Dana C., and Randy L. Jirtle. "Environmental Epigenetics Has Potential For Preventing And Treating Disease." 6 Feb. 2008. Blackwell Publishing Ltd. 22 Nov. 2008 http://www.sciencedaily.com/releases/2008/01/080131151850.htm
Fatemi, S. Hossein. Reelin Glycoprotein : Structure, Biology and Roles in Health and Disease. New York: Springer, 2008. Google Book Search. 22 Nov. 2008 http://books.google.com/books?id=cg0t08bk9syc&printsec=frontcover&dq=reelin+glycoprotein#ppr13,m1
Gallou-Kabani, Catherine, Alexandre Vigè, Marie-Sylvie Gross, and Claudine Junien. "Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond." Clinical Chemistry & Laboratory Medicine 45 (2007): 321-27. Mar. 2007. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=24481803&site=ehost-live&scope=site
Jaenisch, Rudolf, and Adrian Bird. "Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals." Nature Genetics 33 (2003): 245-55. Mar. 2003. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=9184608&site=ehost-live&scope=site
Kaati, Gunnar, Lars O. Bygren, Marcus Pembrey, and Michael Sjöström. "Transgenerational response to nutrition, early life circumstances and longevity." European Journal of Human Genetics 15 (2007): 784-90. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=25463574&site=ehost-live&scope=site
Miller, and Ho. "Environmental Epigenetics and Asthma: Current Concepts and Call for Studies." American Journal of Respiratory and Critical Care Medicine 117 (2008): 567-73. 10 Jan. 2008. American Thoracic Society. 22 Nov. 2008 http://ajrccm.atsjournals.org/cgi/content/abstract/177/6/567
Waterland, Robert A., and Marie-Therese Rached. Scandanavian Journal of Food and Nutrition 50 (2006): 21-26. Dec. 2006. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=23462978&site=ehost-live&scope=site
Weinhold, Bob. "Epigenetics: The Science of Change." Environmental Health Perspectives 114 (2006): A160-167. Mar. 2006. National Institute of Environmental Health Sciences. 22 Nov. 2008 http://www.ehponline.org/members/2006/114-3/focus.html
Whitelaw, Emma. "Epigenetics: Sins of the fathers, and their fathers." European Journal of Human Genetics 14 (2006): 131-32. Feb. 2006. Academic Search Premier. EBSCOhost. 23 Nov. 2008 http://search.ebscohost.com/login.aspx?direct=true&db=aph&an=19473849&site=ehost-live&scope=site
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