Epigenetics is the study of genetic changes in gene expression or cellular phenotype. It refers to functionally pertinent modifications to the genome that do not involve a change in the nucleotide sequence. Such modifications are DNA methylation and histone modification; however, there is no change in the original DNA sequence of the organism; these modifications serve to regulate gene expression without varying the basic DNA sequence. These changes may remain through cell divisions for the rest of the cell's life and may also last for multiple generations.

It was demonstrated that the methylation of mRNA play a decisive role in human energy homeostasis .It is now defined as, "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence."

Molecular Basis

Epigenetic changes can alter the activation of certain genes, but not the sequence of DNA. Additionally, the chromatin

proteins associated with DNA may be activated or silenced. The differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if gene deactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation.

Applications

Paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming,

transvection, maternal effects, the progress of carcinogenesis, and many effects of teratogen.

Molecular biologic techniques used in epigenetic research are regulation of histone modifications and heterochromatin, and cloning, chromatin immunoprecipitation, fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification and bisulfite sequencing bioinformatics (computational epigenetics).

Epigenetic Effects In Humans

Cancer and development abnormalities

Epigenetic carcinogens result in an increased incidence of tumors, but they do not show mutagen activity. Examples

diethylstilbestrol, arsenates, hexachlorobenzene, and nickel compounds.

Vidaza, a formulation of 5-azacytidine (an unmethylalable analog of cytosine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.

Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer. Gene expression in the prostate can be brought under control by nutrition and lifestyle changes.

DNA methylation in cancer

Aberrant DNA methylation is associated with unscheduled gene silencing, and the genes with high levels of 5-

methylcytosine in their promoter region are transcriptionally silent. DNA methylation is essential during embryonic development, and in somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with a high fidelity. Aberrant DNA methylation patterns have been associated with a large number of human malignancies and found in two distinct forms: hypermethylation and hypomethylation compared to normal tissue. Hypermethylation is one of the major epigenetic modifications that repress transcription via promoter region of tumor suppressor genes. Hypermethylation typically occurs at CpG in the promoter region and is associated with gene inactivation. Global hypomethylation has also been implicated in the development and progression of cancer.

Histone variants H2A in cancer

The histone variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many

nuclear processes by altering chromatin structure. A high level of H2A.Z expression is ubiquitously detected in many cancers and is significantly associated with cellular proliferation and genomic instability.

Cancer treatment

Epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy along with radiation and chemotherapy, or could enhance the effects of these current treatments. The epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer. Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer. Drug development has focused mainly on histone acetyltransferase (HAT) and histone deacetylase (HDAC), and has included the introduction to the market of the new pharmaceutical vorinostat, an HDAC inhibitor. Current front-runner candidates for new drug targets are histone lysine methyltransferases (KMT) and protein arginine methyltransferases (PRMT).

A study conducted on patients showed that the use of chemotherapy together with a combination of a DNA methyltransferase (such as epigallocatechin gallate and a histone deacetylase inhibitor (such as valproic acid ) can distinctively modify the malignant transcriptome of blasts by inhibiting DNA hypermethylation and histone acetylation and can confer a positive prognostic impact on patients.

Epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators think epigenetics may ultimately turn out to have a greater role in disease than genetics.

Tags: MET Institute of Pharmacy