Introduction to epigenetic regulation of gene expression
Epigenetics helps in the study of diversity of phenotypes in a population. It can also help in finding different susceptibilities to a disease in cloned animals or monozygotic twins. Epigenetics are considered as heritable changes in gene expression (Esteller 1148). Researchers have found that early life experiences can result in epigenetic effects leading to long-term outcomes in life (Hall 15).
DNA methylation is considered as the best-known epigenetic marker (Esteller 1148). It is the addition of a methyl group to DNA at the 5-carbon of the cytosine pyrimidine ring preceding a guanine (Esteller 1149). It is a kind of genetic modification that can deactivate a gene. Methylation is considered as a component of normal development, but patterns of methylation can vary among individuals (Ahmed S20).
Chromatin and its modification and remodeling.
Chromatin is a readily stainable substance of a cell nucleus consisting of DNA or RNA and various proteins. During the process of mitosis, it condenses into chromosomes. Histone modification and chromatin remodeling are also important processes involved in epigenetic modifications. Histones are the building blocks of nucleosomes, and they undergo various post-translational modifications regulating chromatin structure, DNA repair, and gene expression (Gal-Yam 268). Modification and remodeling of chromatin result in the assembly of active transcription complex having a role in gene activity (Bird 6). Chromatin-remodeling proteins such as SNF2 are found to have significant impact on DNA methylation patterns (8).
Evidence that aberrant epigenetic modification is associated with disease
Research shows that an optimal organization of methylation and chromatin states helps in normal cellular processes (Esteller, and Herman 1). Researchers have found that aberrant epigenetic modification in the form of hypermethylation of tumor suppressor genes can result in the loss of normal cellular function, thereby leading to cancer (Brower S13). Methylation of cytosine present in the dinucleotide CpG is also considered as the most important epigenetic modification in humans (Esteller, and Herman 1).
Epigenetics and Medical Biotechnology
Epigenetics is the study of alterations in the gene function in the genome without changing the DNA sequences that are important building blocks of all species and are used to regulate the genome (Skinner 48R). Epigenetic changes also include inactivation of microRNA (miRNA) genes as a result of DNA methylation. These kinds of epigenetic changes have resulted in the start of several biotechnological projects such as epigenome projects as well as epigenetic treatments (Esteller 1148). Purpose of the epigenome project is to work on all epigenetic modifications, thereby helping in detailed study of normal as well as diseased cells. Cancer Genome Atlas Project has also been initiated to study all the genomic changes taking place in human cancer (Gal-Yam 276).
Epigenetic modifications as biomarkers and use in diagnostic technologies.
CpG islands are involved in about half of all cellular genes (Baylin, and Bestor 299). So, aberrant CpG island methylation can be considered as a biomarker of malignant cells. It can also be used in predicting the behavior of those cells, and can be considered for future studies (Esteller, and Herman 1). Histone methylation is also a marker for both active as well as inactive regions of chromatin (Egger 457). Studies have also shown the use of Arabidopsis mutants as well as chromatin immunoprecipitation in revealing the complexity of the interaction between cytosine and histone H3 methyl K9 methylation, which are considered as epigenetic markers to characterize silent chromatin (Richards R694).
Chromatin immunoprecipitation (ChIP) is found to be an important method in detection of histones or modified histones, or certain other factors related to particular genomic regions. This method is strengthened by PCR amplification of certain regions and/or microarray analysis (Gal-Yam 272).
Drugs that target epigenetic modifiers.
Researchers have reported that it would be better to target epigenetics for the treatment of cancer as it is possible to reactivate epigenetically silenced cancer genes. In this case, 5-aza-2-deoxycytidine or 5-azacytidine and their derivatives have successfully been used to re-express genes silenced by methylation (Esteller, and Herman 4). Initially, their dose was a problem, but researchers started working on reducing the dose of demethylating agents by adding regimen inhibitors of histone deacetylases as, for example, phenylbutyrate (5). Among other epigenetic drugs that act on DNA methylation are procainamide, zebularine, and Psammaplin A. On the other hand, phenylbutyric acid, valproic acid, and depsipeptide act on histone deacetylase. Many of them are still in clinical trials (Egger 460).
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