Hi, welcome back to our lecture on MicroRNAs and epigenetics. And this section will be about epigenetics and environment. The chromatin structure, condensed or open, can be influenced by environmental factors. Such as environmental stress, hypoxia, changes in temperature, radiation, diet, nutrition deprivation, for example, folic acid, which is the main donor of methyl group for DNA methylation and histone methylation. Lifestyle may influence the chromatin structure. For example, smoking and alcohol. And of course, exposure to environmental chemicals, such as particulate matter, pesticides, and metals. The best example that environment may change our epigenome was shown in 2005 by Fraga and his colleagues. The elegant model to study the effects of environment on epigenome is to use monozygotic twins, which are genetically identical individuals. So Fraga et al compared epigenetic patterns in 80 volunteers monozygotic twins, ranging in age from 3 to 74 years old. And they found out that while three years old twins showed very moderate, if any, differences in their epigenome. Their older twins, 50 years and older twins, revealed major variation in their epigenome. And as a consequence of that, the gene expression in these individuals was also changed. That means that different lifestyle of two genetically identical individuals has driven their epigenome apart. Another model to study interplay between environment and epigenetics is agouti mouse. In this model, coat color variation is correlated to epigenetic marks, which I established early in development. And this has been used to investigate the impact of nutritional and environmental influences on the fetal epigenome. The agouti allele is murine metastable epiallele. This means that these alleles are identical alleles that are variably expressed only due to epigenetic modifications. For example, two genetically identical mice, but in one agouti gene is unmethylated, which means it's switched on all the time during development, and this leads to mice which has yellow fur and are obese. However if agouti gene is methylated, meaning that it's switched off during to development, mouse develop brown color of its fur and is normal in size. But if the pregnant agouti mice is fed during its pregnancy with methyl group donors such as folic acid, vitamin B12, choline, and genestein, it will give birth to mainly brown normal-size offspring. While agouti mouse which was fed with normal diet without supplementation will have yellow, obese offspring. This means that the diet of pregnant mouse influence epigenome of its offspring. There are several examples of nutrition and how the nutrition may change the epigenome. For example, as I already mentioned, folate, vitamin B12, methionine, choline, and betaine affect DNA and histone methylation because this is the main donors of methyl groups. And they altered one carbon metabolism. Genestein, which is in soybeans and coffee, and also tea catechin, can also affect DNA methyltransferase and altered epigenome. There are several environmental chemicals which were shown to interact with our epigenome. For example, cadmium interacts with DNA methyltransferases and reduce global DNA methylation. Arsenic use methyl donor, SAM, for detoxification and that leads to global hypomethylation. Nickel triggers de novo DNA methylation and enhance chromatin condensation, which leads in long-term to gene silencing. Chromium perturb methylation and acetylation of histones. And particulate matter was shown to hypermethylate some of the tumor suppressor genes, which can increase risk of cancer development. Previously, we believed that epigenetic inheritance can be only mitotic. It means during cell division epigenetic marks are maintained, and that an embryo epigenome was completely erased and rebuilt from scratch. However, now it's known that some of epigenetic marks remain during embryogenesis, and pass from generation to generation. This epigenetic inheritance is called transgenerational inheritance. This cartoon shows you what I mean by epigenetic inheritance. So if we have F0 generation female which is exposed to the environmental factors. If one generation fetus was also exposed in utero to those factors. And F2 generation germ lines will be exposed to that environmental factor. So in this case, we talked to the multi generation exposure, which last up to two generation. But, if this exposure lead to changes in epigenome in F3 generation, then we talk about transgeneration or phenotype. There are several of environmental chemicals, such as endocrine disruptors, which lead to the changes in epigenome in next three and four generation after exposure of F0 female to those compounds. This means that F3 offspring may have altered epigenome or develop a disease due to exposure to negative environmental factor of its pregnant grand-grandmother. There are several examples of transgeneration epigenetic inheritance in humans, and one of those is hunger during the Second World War in Netherlands. During this year, the calorie consumption dropped dramatically, from 2,000 to 500 per day, and children which where born and raised in this year were smaller, shorter than children born one year before. And they develop several diseases such as edema, anemia, diabetes, and depression. However, these features and diseases last for second and third generation. The children which were born 20, 30 years later after the famine have still these problems. But they were conceived and born during normal dietary state. In this chapter I explained to you the role of environment on epigenetics, and how epigenetics and environment can interplay and influence our genetics.
