Epigenetic, along with genetic mechanisms, is essential for natural evolution and maintenance of specific patterns of gene expression in mammals. Global epigenetic variation is inherited somatically and unlike genetic variation, it is dynamic and reversible. They are somatically associated with known genetic variations.
Recent studies indicate the broad role of epigenetic mechanisms in the initiation and development of cancers, that they are including DNA methylation, histone modifications, nucleosomes changes, non-coding RNAs. The reversible nature of epigenetic changes has led to the emergence of novel epigenetic therapeutic approaches, so that several types of these medications have been approved by the FDA so far.
Epigenetics is defined by inherited somatic changes that are not associated with changes in the DNA sequence. So, the epigenetic outlook of a cell is determined by status of DNA methylation, histones covalent modifications, chromatin structure, and non-coding RNAs and networking with each other.
Epigenetics is of importance because some diseases are caused by defects in the epigenetic system.
For example, a mutation in the DNA methyltransferase 3-A (DNMT3A) enzyme that plays a role in the histone methylation can lead to hematological malignancies such as myelodysplastic syndrome (MDS),3 myeloproliferative neoplasms (MPN)4.
Diseases that have been raised with impaired epigenetic systems are including cancers, diabetes, lupus, asthma, and neurological diseases.
Beyond molecular and structural biology
1. DNA methylation
DNA methylation is a common procedure used to silence genes expression in eukaryotic cells. Recently the importance of DNA methylation in cell biology has been identified, such as embryonic development, inactivation of chromosome X, silencing of genes at different stages of evolution and their expression at appropriate times. DNA methylation is accompanied by the addition of a methyl group to the C5 position of the cytosine ring by DNA methyltransferase (DNMTs).
The mechanisms of silencing gene expression by DNA methylation in the promoters is that specific transcription factors and other transcriptional regulator components cannot access to the promoter, thus DNA expression will be suppressed. By contrast, hypomethylation in this regions will turn on the expression.
Disturbance in DNA methylation is associated with many diseases, such as cancers, lupus, muscular dystrophy and a series of congenital abnormalities.
“Hypomethylation” of DNA is common in cancers. Hypomethylation causes tumorigenesis and cancer by triggering transcription of oncogenes. Also, since methylation causes genome stability, hypomethylation can increase genetic instability by causing genetic mutations in DNA sequence.
On the other hand, many cancers are caused by the “aberrant methylation” of TSG genes, such as P53 and P16 (which are required to regulate normal growth and cellular differentiation), and stop their expression. In addition, the study of the methylation pattern of some genes can determine the response or lack of response to treatment. For example, a specific pattern of hypermethylation in MGMT gene (a type of TSG tumor suppressor gene), may indicate a good response to chemotherapy (alkaloid therapy). “Hypermethylation” in some cancers, such as colon cancer, can be used as an early diagnosis biomarker.
2. Histone modifications:
Histones are highly alkaline proteins packaged in DNA packets called nucleosome. Histone modifications include lysine methylation, arginine methylation, arginine citrullination, lysine acetylation and Serine/Threonine/Tyrosine phosphorylation. Most histone modifications regulate DNA transcription.
- Histone acetylation: Due to histone acetylation the link between the histone and the DNA is weakened and the DNA is removed from the packaging.
- Phosphorylation of histones: This has an effect on the chromatin structure.
- Histone methylation: Histone methylation modifications do not change the charge of histone protein, but affect the affinity of the genome transcription factors. The histone methylation can activate or restrict transcription.
Disruption in the function of methyltransferase enzymes can lead to changes in the site and the number of methylation and, as a result, has an important role in the development of malignancies.
“Radiation therapy” is a widely used method to treat human malignancies, but in some tumors, including glioma tumors, radiation induced a breakdown in tow strand DNA leads to epigenetic changes results in increased histones methylation. As a result of histones methylation, the DNA structure is changed and DNA repairing proteins are recruited, which leads to resistance to radiotherapy.
Gursoy-Yuzugullu et al. Found that the use of the methyltransferase inhibitor SETD8 H4K20 (UNC-0379) and the G9a H3K9 methyltransferase inhibitor (BIX-01294) are effective method to increase the sensitivity of human glioma cells to radiotherapy. However, UNC-0379 by inhibiting H4K20 methylation and reducing the use of 53BP1 protein in the fracture site of two DSB sequences causes a slight increase in sensitivity to radiotherapy, while BIX-01294 inhibits H3K9 methylation and increases the sensitivity to radiotherapy by inhibiting G9a. It has been shown that inhibiting H3K9 methylation by inhibiting G9a makes glioma cells extremely sensitive to radiotherapy by inhibiting G9a. It has been shown that inhibiting H3K9 methylation by inhibiting G9a makes glioma cells extremely sensitive to radiotherapy.
MiRNAs are a class of non-coding RNAs (ncRNAs). They play critical roles in regulating functions of the cells, disruption in their structure and turnover can causes diseases. Such miRNAs that somehow have an oncogenic role are called Onco-miRs.
The miR-101 reduces EZH2 expression. In several types of cancer, the amount of miR-101 decrease. In case of increase in the expression of miR-101, the process of disease will be reversed and the growth of cancerous cells will stop.
MiRNAs is also a cancer diagnosis biomarker and also determinant of cancer prognosis and patient overall survival.
MiRNAs can be used to classify myeloid malignancies. Induction of miRNAs into malignant stem cells inhibits malignancy by suppressing production of specific proteins. But due to the lack of a suitable in vivo carrier for an accurate transmission of miRNA to the cells and presence of various barriers in the body, this type of treatment needs more evolution.
4. Epigenetics and cytotoxic treatments:
One of the problems with traditional chemotherapy is that sometime after treatment, cancerous cells undergo acute epigenetic changes due to the cytotoxicity of chemotherapy that promotes resistance to therapy, proliferation of malignant cells, and if the cytotoxic therapy is stopped, the cancerous cells will reproliferate. It has now been shown that the use of chemotherapy drugs such as low dosages of azacitidine by improving epigenetic modifications and having non-toxicity for bone marrow, is a more appropriate treatment than high dosages of drugs.
The combination of epigenetic therapy and chemotherapy will reinduce the response to chemotherapy and resolve the resistance to cytotoxic agents.
It is new scientific frontier in research and more evidences being established to solve the mystery of cancer and overhaul the outcomes of cancer treatment, a science behind precision medicine.