Week 8 - Epigenetics

Epigenetics Milly Ryan-Harshman, PhD, RD Epigenetics: Definition Epigenetic changes are those heritable changes in gene expression that do not require changes in DNA sequence. Many effects are considered epigenetic if, without mutation, they change the long-term physiological, metabolic or anatomical state of plants or animals even if the specific gene expression has not been identified. Epigenetics: Definition Epigenetics may be the bridge between nature and nurture. Twins may be identical genetically, but not epigenetically. Why? The environmental influences on twins will differ, affecting gene expression. How does this work? Epigenetics: Definition First, the complex of DNA and protein in the nucleus of a cell is known as chromatin. The DNA associated proteins are known as histones. Structural changes can occur to the DNA, to the histones, or to the chromatin. These changes, which include DNA methylation and histone acetylation, are basically epigenetic tools that keep DNA packaged in such a way as to keep genes active or silenced as required. Epigenetics: Definition Epigenetic modifications do not change (i.e., mutate) DNA, but influence the availability of the code to the factors that transcribe and translate the code into its products. Epigenetic tools essentially govern the genetic blueprint. DNA may be the code of life, but it requires a living organism and that organism’s interaction with its environment to be of any real value. Epigenetics: Three Examples Imprinting – the tale of the horse and the donkey Mouse coat colour – environmental impact “Star” foxes – friendly furballs illustrate another kind of epigenetics Epigenetics: Imprinting Inheritance of parental germline DNA methylation patterns by offspring is called genomic imprinting. The addition of methyl groups to DNA can be used to distinguish the gene copy inherited from the father from that of the mother, as well as to tell the cell which copy to use to make proteins. Epigenetics: Imprinting “Imprinted genes” do not rely on the laws of Mendelian genetics, where both parental copies are just as likely to contribute to the outcome. The effects of imprinted genes can be seen in breeding experiments to create mules. Crossing a male horse and a female donkey created a different animal than breeding a female horse with a male donkey. Imprinting abnormalities may be involved in the disease process. For example, some tumour suppressor genes are maternally expressed genes that are mistakenly turned off, preventing the production of a protein that limits growth, allowing cancer to develop. Epigenetics: Mouse Coat Colour Mice that are genetically identical can have different coat colour patterns depending upon the degree of agouti gene expression. A black “normal” mouse has no agouti expression. A yellow mouse has agouti overexpression. A mottled mouse is somewhere in between according to its mottling. Epigenetics: Mouse Coat Colour What scientists have noted is that the yellow mice have increased metabolic efficiency, converting food calories to fat stores more easily. Yellow mice have been bred that are obese, hyperinsulinemic, and diabetic. Their health status is due to agouti overexpression, which can also make them more susceptible to certain types of cancers as well as shorten their life span. Maternal epigenetics can be partially passed on to the next generation by maternal epigenetic inheritance. Would it be possible to control diabetic inheritance by some sort of agouti gene silencing? In mice? In humans? Epigenetics: “Star” Foxes Inheritance of somatic DNA methylation patterns from parents to offspring is called transgenerational epigenetic inheritance. Silver-black foxes are used for their fur and have been domesticated. Breeders choose foxes that are friendly to humans and otherwise behave like domesticated dogs to produce more foxes. Epigenetics: “Star” Foxes In the 1970s, it was noted that the domesticated foxes had white spots or “stars” on the tops of their heads between their ears. This coat colour phenotype occurred too frequently and independently to be caused by a mutation; also, the foxes’ ancestors did not have the star phenotype. Epigenetics: “Star” Foxes Selective breeding resulted in a star allele that does not follow Mendelian laws of segregation. Star expression appears to be inherited epigenetically in domesticated foxes. There are also differences in the expression of star depending on the sex of the parent from whom star is received; thus, star is also imprinted. Epigenetics: “Star” Foxes Although unknown, the nature of the parental effects that accompany domestication and lead to changes in offspring and the domesticated fox population is of considerable scientific interest. Epigenetics: The Maternal Role Maternal nutrition affects long-term, even multigenerational, health because of persistent changes in offspring. When in short supply, nutrients are allocated toward short-term survival and reproduction. Even when a nutrient is plentiful, its main allocation will be toward reproduction. What this means is that long-term health is less important to the body’s metabolic processes than short-term survival. Epigenetics: The Maternal Role Adult levels of DNA methylation depend on adult nutritional factors such as dietary folate, methionine and choline, and metabolic factors such as homocysteine and S-adenosylhomocysteine (SAH). Low levels of folate and high homocysteine (HCY) levels during pregnancy probably cause NTDs in humans, though the molecular mechanism is unknown. Epigenetics: The Maternal Role What is known is that nutritional and metabolic effects are important in embryonic and fetal development. Some maternal effects can have lifelong consequences for the offspring and for subsequent generations. Gene regulation by methylation of DNA and of histones may depend on adequate levels of dietary precursors for methyl metabolism. Epigenetics: The Maternal Role Some metabolic diseases, such as homocysteinuria, help to point out alleles whose effects are less severe, but still take a heavy toll over time or during pregnancy. In homocysteinuria, methyl metabolism is severely compromised, but using nutrient balances that allow the genetic and enzymatic deficiencies to be bypassed in alternative pathways improves patient health and survival. Epigenetics: The Maternal Role More “moderate” genetic predispositions, such as increased risk for CVD or dementia, could be compensated for by increasing total folic acid intake. However, an interesting question would be whether or not such “tinkering” could result in an epigenetic change that could lead to highly folate dependent individuals who would have difficulty meeting their needs. Epigenetics: The Maternal Role Long-term effects of maternal nutrition and metabolism have been linked to diabetes and cancer, but long-term memory and mental function can also be influenced. When pregnant rats were fed a normal, adequate diet plus a choline supplement, their offspring had a better memory that did not decline with age than offspring of pregnant control rats. The use of compounds for maternal effects on offspring are of scientific interest, but likely complex. Epigenetics: The Role of Diet Variations in the human diet for nutrients important in methyl metabolism can be significant. A diet of hamburgers, fries and cola provides significantly less folate, vitamin B12, zinc, choline, betaine, and methionine than a diet of salmon, broccoli, spinach, and wheat germ. The desired effect of nutrients on DNA methylation depends on the genes in question and on whether the target cell is a normal cell or a cancer cell. However, the effects of certain nutrients on DNA methylation and gene expression is of major scientific interest. Homocysteine Metabolism Nutrient (mg) Hamburger, Fries, Cola Salmon, Broccoli, Spinach, Wheat Germ Folate 0.26 2.1 Vitamin B12 0.003 0.029 Zinc 8 42 Choline 170 880 Betaine 90 5300 Methionine 820 5100 Epistasis Epistasis, or gene-gene interactions, explains how genetic ancestry is important to understanding gene-nutrient or gene-disease interactions, and ultimately, health and disease. Epistasis refers to at least two genes that are not alleles of each other interacting to have a measurable effect on a trait. Alleles of one gene can be dominant to alleles of another gene, making the outcome difficult to predict. Example: Labrador retriever coat colour Epistasis Suppose there are two obesity genes. Gene X and gene Y. For gene X, the homozygous alleles are represented by AA, and the heterozygous alleles by AB. For gene Y, it’s CC and CD. Now suppose it takes both heterozygous alleles interacting with one another to cause obesity. Then, only in those with the AB/CD will obesity occur. A gene-diet interaction would complicate matters because an individual with obesity gene X may be normal weight when a low fat diet is followed, but become obese with a high fat diet in combination with the heterozygous allele (high fat/ AB). Is it possible to predict the weight of an individual with AB/CD/high fat?