The literal meaning of the term epigenetic is “close to, on top of, outside of, or in addition to genetics” (from the Greek ἐπι – epi).
The series of chemical tags that modify the human genome (20,000 genes consisting of over 3 billion base pairs) constitute the epigenome, and include any factor, outside of the gene itself, which modifies how a gene expresses itself. The epigenome integrates the information encoded in the genome with all the molecular and chemical cues of cellular, extracellular, and environmental origin. Along with the genome, the epigenome determines the unique gene expression program of each cell type to define its observed expression in health or disease.Genes hold the blueprints; epigenetic factors direct how the details of those blueprints are carried out.
For nearly a century after the term “epigenetics” first surfaced in the scientific literature, researchers have poked around in the shadowy recesses of the gene, trying to confirm the suspicion that gene function could be altered by more than just changes in sequence (point mutations, deletions, etc.). Today, an increasing number of illnesses, behaviors, and other positive and negative health states already have been linked to epigenetic mechanisms, including cancers of almost all types, cognitive function, and respiratory, cardiovascular, reproductive, autoimmune, neurobehavioral illnesses and even consciousness itself. Known or purported effectors behind epigenetic processes include many agents, including heavy metals, pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria, basic nutrients, meditation, and emotional state.
The epigenome also, in some sense, represents the ability of an organism to adapt and evolve through expression of a set of characteristics (phenotypes) developed in response to environmental stimuli. Ultimately, it works both ways: the environment presents various factors that influence the epigenome, and the unique epigenetic and genetic profile of each individual in turn modulates the specific response to these factors (Figure 1).
Figure 1. Epigenetic influences in humans.
The figure represents a compilation of the various epigenetic influences on humans by different sources present in the environment. While some of these might be beneficial for health and behavior, others are known to be harmful.
Many types of epigenetic processes have been identified—they include methylation, acetylation, phosphorylation, ubiquitylation, and sumolyation. Other epigenetic mechanisms and considerations are likely to surface as work proceeds. Epigenetic processes are natural and essential to many organism functions and can promote longevity and human evolution, but if they occur incorrectly, there can be major adverse health and behavioral effects.
Perhaps the best known epigenetic process, in part because it has been easiest to study with existing technology, is DNA methylation. This is the addition or removal of a methyl group (CH3), predominantly where cytosine bases occur consecutively. DNA methylation was first confirmed to occur in human cancer in 1983, and has since been observed in many other illnesses and health conditions.
Another significant epigenetic process is chromatin modification. Chromatin is the complex of proteins (histones) and DNA that is tightly bundled to fit into the nucleus. The complex can be modified by substances such as acetyl groups (in a process called acetylation), enzymes, and some forms of RNA such as microRNAs (mi-RNA) and small interfering RNAs (si-RNA). This modification alters chromatin folding structure to influence gene expression. In general, tightly folded chromatin tends to be shut down, or not expressed, while more open chromatin is functional, or expressed.
In the past several years, and especially in the past year or two, a few groundbreaking studies have focused fresh attention on epigenetics as it relates to Ayurveda. Dr. Gerson began collaborative efforts along these lines in 2003 and coined the term “ayuepigenomics”.
Despite the potentially huge role that epigenetics may play in human disease, investment in this area of study remains tiny compared to that devoted to traditional genetics work.
Our proposed study will investigate the epigenetic mechanisms of action involved in the anticancer activity observed in water and alcohol extracts of ashwagandha leaf (Withania somnifera Dunal).
Ashwagandha (Withania somnifera Dunal) is an important and popular Ayurvedic plant used in Ayurvedic medicine. It has been shown to possess various therapeutic and health-promoting potentials of which the molecular mechanism(s) remain obscure. In addition to older studies which have shown Ashwagandha to possess anti-stress, anti-aging and neuro-protective activities, newer studies have found that the alcoholic and water extracts of Ashwagandha leaves possess considerable anticancer activity in cancer cells while normal cells remain unaffected. Bioactive components for these activities were identified as: Withanolides, Withanone and Withaferin A in the alcoholic extract, and triethylene glycol in the water extract.
In cell culture models, these components caused cytotoxicity to a variety of human cancer cells. Preliminary insights into their mechanism of action revealed that they cause (i) activation of tumor suppressor genes p53 and pRB, (ii) induction of oxidative stress and (iii) MMP-3 and MMP-9 (metalloproteins which regulate tumor metastasis) are down-regulated in cancer cells while normal cells remain unaffected.
However, we still do not know how Ashwagandha extracts act at the molecular level to bring about these effects. Evidence strongly suggests that these may likely be epigenetic effects and no doubt a systems biology paradigm plays a major role.
The proposed study seeks to discover and elucidate these specific epigenetic modifications. This knowledge can easily and relatively quickly lead to the production of a low-cost, readily available anticancer medicine especially where modern medicine is either not available, ineffective or is limited by severe side effects. For additional technical background on this study click here.