Role Of Epigenetic Changes On Future Generations Literature Reviews Example
Type of paper: Literature Review
Topic: Genetics, DNA, Stem, Health, Medicine, Development, Drugs, Cancer
The genetic information of a cell is coded in its DNA sequences. A base change in this DNA sequence causes a corresponding change in the genotype and the corresponding phenotype. These changes are often inherited by the progeny cell during cell division. Now we know that phenotype is not just influenced by the genetic information stored in the DNA sequence, but also the micro and macro environment of the cells. Two identical DNA sequence can give different phenotypes in different environment. Even two genetically identical twins when raised in different environment can show a number of variations. Phenotypic plasticity is the term which is used to indicate the influence of phenotype by the genotype. If the environmental influence is stronger on the phenotype, when compared to the genotype, the phenotypic plasticity of the gene is considered high. When the phenotype can be readily identified by its genotype, then it is said be of low plasticity. The cells are capable of transmitting non genetic component of its phenotype to the next generation. This has given rise to the field of epigenetic. Epigenetics is the study of inherited changes in the phenotype or gene expression caused by mechanism other than changes in the underlying DNA sequence. The epigenetic messages in the cell are coded in the form of DNA methylation, histone modifications (acetylation, methylation), and non coding RNAs (e.g: micro RNA). For example, DNA methylation at C-5 position of cytosine in CpG dinucleotide is associated with modification in gene function. Epigenetic changes are capable of activating and silencing genes without changing the DNA base sequence. When histone is tagged with an acetyl group, it opens up the tightly wound chromatin, and thus genes coded by this chromatin, becomes accessible for transcription and translation, and are said to be activated. Like wise when the histone is deacetylated, the chromatin condenses and the genes coded by the corresponding chromatin are silenced. Like wise non-coding RNAs can be cleaved and used to silence protein coding RNAs. Cellular differentiation, X-chromosome inactivation and imprinting are a few examples of epigenetic regulated phenomenon. Emerging research evidences, indicate that epigenetics is associated with processes like hormonal regulation, differentiation, apoptosis, cell cycle, carcinogen metabolism and DNA repair. Epigenetic changes are influenced by prenatal and post natal environment and can modify our risk of developing diseases. Nutrition, xenobiotic chemicals, behavioral factors, reproductive factors and hormonal exposures can cause epigenetic alterations. The present scenarios of epigenetic research and its future prospective and impact are reviewed in this article. (Chadwick & Gail)
2. Review of literature:
2.1 Epigenetics and inheritance:
Just like genetic information that is passed on from one generation to the next, the epigenetic changes are also passed from one generation to the next. This means that the environmental experiences of the parents can be passed on to the offspring’s in the form of epigenetic tags. Though scientists have not yet demonstrated the mechanism by which this takes place, most scientists believe that epigenetics tags can be inherited. For the epigenetic information to be transmitted to the next generation, it must overcome the reprogramming that happens during fertilization. During fertilization, and the subsequent development process, all the epigenetic tags in the DNA are erased. However certain epigenetic tags escape this erasing process, that happens in the reprogramming stage, and manages to pass on to the embryo. The other feature of epigenetic is that they are transient in comparison to the relatively fixed DNA code. An epigenetic change that was triggered by the environmental conditions could be reversed in certain instances, by other environmental conditions or by removing the environmental variable which was responsible for the epigenetic change in the first place.
2.2 Epigenetic and development: Identical twins are not exactly identical. They have different personalities, difference susceptibility to different diseases, e.g one may succumb to cancer, while other may die from heart diseases. Though the identical twins are clones, they can have different epigenetic codes associated with difference in diet, lifestyle and environmental toxins they are exposed to. Epigenetic programming, in a cell starts even before birth. Epigenetic changes are important in choreographing different stages in cell development. An embryonic cell is capable of developing into red blood cell or a variety of white blood cell. Once it has committed to becoming a red cell, it shut down the gene needed for developing into white blood cells. Epigenetic changes help in these processes. Evidence from animal studies, suggests that, the epigenetic deregulation happening during the development process, can contribute to the occurrence of diseases in later life. Thus epigenetic is responsible for developmental origin of diseases. Sheep which were deprived of nutrients like folate, vitamin B6 and vitamin B12 during early development ,were more fatter and had high blood pressure. Thus a mother’s diet can influence epigenetic changes in the foetus. Unlike gene mutations, epigenetic fate is not sealed at birth. Sensible choice of food in later life could reverse the epigenetic changes that happen during development. (Kiefer)
2.3 Epigenetics in cancer cause and cure: Cancer is associated with deregulation in gene expression: a tumor suppressor gene is silenced or an oncogene is activated in the process. Epigenetic machinery is very critical for gene regulation and many cancers are now linked to disruption of the epigenetic machinery. Changes like hypomethylation or hypermethylation of CpG island and histone modifications can cause changes in gene expression, and are thought to contribute to tumor formations, by either silencing a tumor suppressor or activating an oncogene. The understanding that, epigenetic play a role in cancer has led to the development of epigenetic therapy. The first successful drugs in this line were DNA methyl transferase inhibitors. Later histone deacetylase inhibitors and histone methyltransferase drugs were used in treating cancer. All these class of drugs can reverse gene silencing, and demonstrated anti-tumor activity. At low doses these drugs do not inhibit normal proliferation, but can inhibit tumor growth. Azacitidine was the first hypomethylating agent approved by the FDA. Decitabine is yet another successful drug in treating certain types of cancer. Both these drugs produced remission in 30% of the patients. Though these drugs have relatively less side effects, the improvement with these drugs is slow and requires multiple drug therapy. Many other epigenome modifying drugs which treat epigenetic modification in diseases are still in phase I clinical trial, and if successful will enter the future drug market. (Esteller)
Stem cell epigenetic: Human embryonic stem cells are derived from cells in an embryo. These embryonic cells go through an active period of epigenetic remodeling which is responsible for their pluripotent nature. The best known factors that determine the pattern of gene expression in a cell are: DNA methylation, transcription factors and changes in chromatin structure. A balance of epigenetic factors along with other transcription and chromatin remodeling factor decide pluripotency status and differentiation status of the cell. Embryonic stem cells are important models to study epigenetic phenomenon. As the cell differentiates there are epigenetic modifications happening in the cell, which causes it to lose pluripotency and become a differentiated cell. Understanding the role of epigenetic regulation in embryonic stem cells will allow us to direct the cell differentiation according to future research or clinical needs. (Bibikova)
While there are many ethical issues in obtaining and using embryonic stem cell, induced pluripotent stem cells have been an effective replacement for the former. Induced pluripotent stem cells are created by converted a differentiated somatic cell to a pluripotent stem cell. To do this, the somatic cells are either grown in the midst of cells from the blastocyst or are subjected to a transient stress like low pH, which causes a reprogramming in the cells gene expression profile (Obokata, et al). Hypomethylation was observed in the region of the pluripotency marker genes. When compared to embryonic stem cell, induced pluripotent stem cells retain some of the memory of the donor cell. These studies suggest that epigenetic programming determines the fate of a cell, and it could be reversed using strong environmental cues. (Bibikova, et al.)
Pluripotent stem cell, unlike the embryonic stem cell, has a greater propensity to carry epigenetic memory which can influence it fate while differentiating. This proved a hindrance in differentiating pluripotent stem cells to cells of ones choice. Deng was the first to report the difference in the methylation pattern between three lines of pluripotent stem cells. Later studies confirmed that these cells retain some of the epigenetic marks of the donor cells. However certain groups of scientist didn’t agree with this conclusion, as they failed to observe any difference in the embryonic stem cells and pleuripotent stem cells themselves. They argued that the difference in methylation could be a result of different induction or cell culture procedure. To settle this argument, Hu in 2010 performed in-vivo directed neural differentiation in 5 human embryonic stem cell lines and 12 induced Pluripotent stem cell clones and showed that the embryonic stem cells were more than 90% efficient in differentiation, while induced pleuripotent stem cells had very poor differentiation potential, which is likely the result of epigenetic memory in induced pluripotent stem cells. Researchers were able to demonstrate, that, by changing the levels and stoichiometry of reprogramming factors and culture conditions it is possible to alter the epigenetic state of the induced pluripotent stem cells. (Kim, et al.)
Epigenetic and psychology: Evidences suggest that epigenetic regulations are important in the etiology of many psychiatric disorders. Though a strong family history is noticed in many psychiatric disorders, it has been difficult to associate these diseases with gene mutations. However many feature of psychiatric disorders are consistent with an epigenetic involvement. These features include: discordance in monozygotic twins, late age of onset, parent-of-origin and sex effects, and fluctuating disease course. An organism’s epigenome is more dynamic than its DNA sequence. Epigenetic mechanism regulates the expression of information in the DNA sequence, without actually altering the base sequence. Thus “epigenetic mutations” can be harmful even in the absence of a DNA mutation. Epigenetic regulation is required for proper genomic functions, like, regulation of gene activity, inactivation of parasitic DNA elements, and chromosomal segregation. Deregulations in this mechanism can be harmful. Major psychosis like schizophrenia and bi-polar disorder are multifactorial, and the clinical features of these diseases are often multifaceted. Mills was the first to study the epigenetic involvement in psychosis like schizophrenia and bipolar disorders. He observed differences in the methylation pattern around glutamate transporter genes and GABA receptor genes in schizophrenic patients. Drugs that act by modifying the epigenome could be of much value in treating such disorder. Valproate, a drug which has mood stabilizing and anticonvulsant activity, also has the property to modify the epigenome, by its histone deacetylase activity. This drug is found to be very useful in improving cognitive function. Identifying the interplay between epigenetic, DNA sequences, and environment should become the focus of future work in identifying diseases etiology in psychiatry field. Like wise developing new treatment strategies that could address the epigenetic deregulation associated with the diseases could be beneficial. (Masterpasqua)
Role of nutrients in modifying the epigenome: The nature of nutrients we take can alter the epigenome and thereby modify our risk to developing diseases. Nutritional intervention can modify certain epigenetic deregulation, by inhibiting certain enzymes that are responsible for DNA methylation or histone modification, and thereby improve health. In this regard, nutritional epigenetic is viewed as an attractive tool to prevent developmental diseases, cancer and other lifestyle associated diseases. Folate, vitamin B-12, methionine, choline, and betaine can affect DNA methylation and histone methylation by altering 1-carbon metabolism. Water-soluble B vitamins like biotin, niacin, and pantothenic acid, play important roles in histone modifications. Biotin is a substrate for histone biotinylation. Pantothenic acid is a part of CoA to form acetyl-CoA, which is the source of acetyl group in histone acetylation. Curcumin inhibits histone acetyltransferases (HAT). However our current knowledge in the area of nutritional epigenetic is limited and further studies are required to understand the use of nutrients or bioactive food components in maintaining health and preventing diseases through modifiable epigenetic mechanisms. We also need to determine the association between early nutritional exposure and later health consequences. (Simmons)
Future of epigenetic in aging: The chromatin structure is not fixed and is subject to age related remodeling. DNA plasticity is in part mediated by the epigenetic changes. A number of studies show that epigenetic processes are involved in the process of aging. Changes in DNA methylation is associated with age related diseases. Aging was associated with hypomethylation of GCR, iNOS and TLR2 and increased methylation of IFNγ, F3, CRAT and OGG. Hypomethylation was also noticed in gene like WRN and lamin A/C genes with have a dual role in tumor suppression and progeria. There is a decline of immune-competence with age. Aging of the immune cells is associated with a decline of both T cell and B cells function. This is associated with increased susceptibility of aged individuals to autoimmunity and neoplasia. Epigenetic changes could have a role to play in the pathogenesis of these diseases. Aging epigenetic is an emerging field, which promises exciting revelation in the near future. (Gonzalo)
Epigenetics and lifestyle: Lifestyle involves nutrition, behavior, stress, physical activity, working habits, smoking habits, alcohol consumption, etc. Evidences indicate that lifestyle related factors like, diet, obesity, physical activity, tobacco smoking, alcohol consumption can modify a persons epigenetic pattern, and affects his risk to cancer, cardiovascular, respiratory and neurodegenerative diseases. Obesity was associated with difference of methylation pattern in genes involved in adipogenesis and inflammation. While most of the studies pertaining to lifestyle and epigenetic were limited to identifying difference in methylation pattern, a more exhaustive study and evidence will be required to associate specific life style factors with health.(Alegria-Torres, Baccarelli and Bollati)
Conclusion: Emerging wealth of new data and knowledge in the area of epigenetic indicates that the future of epigenetic is bright. However we need technologies to generate data by sequencing of the epigenome and techniques to maintain and manipulate the data produced by these sequencing technologies. As more epigenetic markers are associated with diseases we will require new strategy to diagnose patients based on these variations. Several drugs which can modify the epigenome are used in treatment of disease like cancer, however these drug lack specificity and efficacy. So developing better drugs is another future challenge in this area. There is still a lot of gap in our understanding on how epigenetic modification affects embryo development. Understanding epigenetic patterns in stem cells will help us reprogram the gene expression and convert differentiated cell to pluripotent stem cells. Like wise, the mechanism by which the epigenetic marks are inherited from the parent is transferred to the offspring is not known. Like wise epigenetic could explain future evolution of human race. Epigenetic has the potential to transform health care and provide better lives.
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