The term 'epigenetics' was first proposed by Conrad Waddington (1905-1975) to call together the study of the processes by which the genetic information of an organism, defined as genotype, interacts with the environment in order to produce its observed traits, defined as phenotype. The interaction of the gene and its reaction was not given much importance and was grossly ignored as almost passive. The epigenetic got momentum in recent times when it was demonstrated the Dorsophilia melanogaster, fruit fly changed its colour of eye to red, when its egg was exposed to temperature 37 degree Celsius instead of 25 degree Celsius. It demonstrated the impact of environment on gene expression which is called nurture. Although everybody guessed the influence of environmental conditions on gene function, there was no clear understanding how these changes could be happening. It has become clearer that everything that happens in cell is not out of a dominant DNA, but there exists cross talks between various pathways and the outcome decision is resultant of this.
The availability of refined analytical tools and advancement in human genome and molecular biology techniques has given impetus to new branch of biotechnology, the epigenetic. The epigenetic is a novel concept involving a systematic approach of study to find out how the nature and nurture interact to give outcomes like disease. It is an attempt to find molecular basis for chronic diseases like hypertension, diabetes mellitus, cancer and viral infections. Epigenetic examines the inheritance characteristics which are not due to DNA expression, but beyond it. These changes do happen outside the nucleus, when regular gene expression control gets interfered with environmental changes. The epigenetic approach has capability for deciphering the etiology of almost all diseases like essential hypertension and cancer. The field of epigenetic is highly complex and needs elaborate research efforts. The epigenetic can broadly described as the bridge between genotype and phenotype. It is described as phenomenon of change in protein expression (phenotype) without affecting the DNA sequence. It challenges the common dogma that all phenotype gene expressions has genotype (nucleus based DNA) basis. For example in all multi cellular organism, diversity of cell types happens although originally there is common genotype. For example cells of the muscles, nerve and bone have common origin and share the same genotype but vary in phenotype. Hence, the cellular differentiation phenomenon can be described as natural epigenetic.
Mechanisms of genotype to phenotype expression
The most important task is to understand the mechanisms of genotype to phenotype expressions. What happens in between was so for a qualitatively described and the in recent times quantitative analysis how, why, when and while are explained by studying the chromatin. The chromatin is the complex of DNA and its intimately associated proteins called histone. The study of chromatin function is deciphering the secrets of epigenetic. It is also understood that the part of the chromatin function is conserved and other are subject to be influenced by the environment. The molecular basis of epigenetic is naturally achieved by chemical changes that happen in chromatin. The DNA methylation is perhaps the most common chemical modification of chromatin leading to epigenetic changes. There are many possibilities of variety of covalent and non covalent mechanisms on the histone of chromatin being the basis of epigenetic. There are several examples of acetylation and phoshorylations that happens in chromatin leading to its change in physical and biological properties. The example for non covalent mechanisms such as chromatin remodelling and incorporation of unique histone leading to variation of chromatin template. The covalent modification of chromatin, nucleosome remodelling and introducing variant histone all work in symphony, to introduce meaningful variation in the chromatin leading to definite phenotype. The Recent finding of role of non coding RNA in epigenetic is interesting. The RNA interference as post transcriptional gene silencing has been well established mechanisms of explaining the epigenetic. There are many interesting molecules like micro RNA and other path ways which have epigenetic link.
Epigenetic is an exciting area of research that has the potential for effective new therapies in the areas of unmet medical need and new diagnostic, screening or pharmacoepigenomic tests. The new drugs and diagnostics based on epigenetic mechanisms are already available in market which has produced commercial products. Scientists have now identified large numbers of individual enzymes responsible for making specific alterations to histones and these are the focus of drug discovery efforts. The whole epigenome maps will be made freely available which has the potential to uncover new drug targets miRNA is also a growing field in terms of both therapeutic and diagnostic development For example the enzyme such as histone methylases and demethylases, histone acetylases, and readers (bromodomains and chromodomains).
As large number of proteins are involved in cancer function through the modification of chromatin structures, interfering with normal chromatin function. For this reason, the chromatin is emerging as a prime target for the therapeutic intervention of many chronic illnesses like cancer, essential hypertension, diabetes, asthama, COPD. These drugs focus mainly on the treatment of cancer, neurodegenerative and infectious diseases although research is underway to explore the role for epigenetic in cardiovascular, metabolic, ocular and other diseases. Current pan- and class-selective histone deacetylase inhibitors will be improved upon by the next generation of selective inhibitors. These offer perhaps the greatest potential as they may be applicable outside the oncology arena where the burden of toxicity must be low. The development of this generation of targeted compounds will be undertaken alongside companion diagnostic tests, helping to generate the best outcomes for individual patients in the future. Epigenetic biomarkers based diagnostic tests will enter the market. These tests will focus on cancer and will progress from tissue or fine needle aspirate-based diagnostic tests to a far less invasive bodily fluid (blood, sputum, urine) based screening. Prognostic markers that will guide treatment decisions are also on the horizon.
(The authors are with Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka 576104)