Epigenetics and Integrative Natural Remedies

Epigenetics, in simple terms, is the secret sauce or the glue that bridges many natural remedies with scientific plausibility. This is all about activation and deactivation of genes that are both “good” and “bad” for your health, which can occur through diet, supplements, herbs, drugs, and literally anything in your environment including your own thoughts and emotions.

So what does this mean? It means that you are NOT simply a “victim” of genetic determinism. You are not simply living out your life according to how the genes you were born with programmed you. Instead YOU are in control of 95% of your own health. Why 95% and not 100%? Because in about 5% of situations you may have inherited a particularly strong genetic predisposition to certain rare diseases and will require a whole lot more than clean living to stay healthy. However, the rest of the time it turns out that you are very much in control. Fully 95% of the time there is a delicate balance between what you are born with and what you actually do to your body.

Epigenetics refers to changes in gene expression caused by mechanisms other than changes in the actual DNA nucleotide sequence. That’s how the name epi- (Greek: over; above) -genetics came about. These changes may remain through cell divisions for the remainder of the cell’s life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism;^[1] instead, non-genetic factors cause the organism’s genes to behave (or “express themselves”) differently.^[2]

The best example of epigenetic changes is the process of cellular differentiation, which means cells go from stem cells that can do anything to “differentiated” or “different” cells that make up different organs and tissues. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.^[3] Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.^[7]

Two predominant epigenetic mechanisms are DNA methylation and histone modification. Both of these processes can be modified by dietary nutrients, herbal component phytotherapy and supplements of various types. It bears repeating that they can also be influenced by stress and other environmental factors.

Molecular basis of epigenetics

The molecular basis of epigenetics is complex. It involves modifications of the activation of certain genes, but not the basic structure of DNA. Additionally, the chromatin proteins associated with DNA may be activated or silenced. This accounts for why 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 a mutation in the DNA has been caused, some epigenetic changes are inherited from one generation to the next.^[9]

Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID) and bisulfite sequencing. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics). You DO NOT have to understand what this all means. But you SHOULD be in awe as to how detailed the symphony of life at the sub-cellular level is and how it takes very intricate biochemical and molecular tools to unravel the truth.

Mechanisms

DNA methylation and chromatin remodeling

Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone proteins with which it associates. Histone proteins are little spheres that DNA wraps around. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:

The first way is post translational modification of the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If the amino acids that are in the chain are changed, the shape of the histone sphere might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around it, these modified histones would ensure that a differentiated cell would stay differentiated, and not convert back into being a stem cell.
The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing up with a G, so in the next round of cell division it will be replaced with a regular C. However, some areas of genome are methylated heavier than others and highly methylated areas tend to be transcriptionally less active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from this parent (genetic imprinting).

Development

Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodeling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a “memory”. In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types (“totipotency” and “multipotency”). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodeling, it has been hypothesised that plant cells do not have “memories”, resetting their gene expression patterns at each cell division using positional information from the environment and surrounding cells to determine their fate.^[30]

Integrative Medicine Implications

Epigenetics has many and varied potential health and medical applications. Congenital genetic disease is well understood, but it is now also clear that epigenetics can play a major role in how your actions and relationship to your environment affects your health in developing non-congenital and non-heritable diseases. Learning exactly how these epigenetic mechanisms turn on “good” genes and turn off “bad” genes is the new Holy Grail and we are learning more exponentially as molecular tools get better and better. Meanwhile, we know more than enough to guide the average human towards decades more of productive quality of life years.

Notes and references

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^ Special report: ‘What genes remember’ by Philip Hunter | Prospect Magazine May 2008 issue 146
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^ Roloff, T.C., Nuber, U.A., 2005 Chromatin , epigenetics and stem cells. Eur J Cell Biol. 84, 123-135
^ C.H. Waddington (1942) (1977). “The epigenotype”. Endeavour 1: 18–20. doi:10.1016/0160-9327(77)90005-9.
^ Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471
^ Russo, V.E.A., Martienssen, R.A., Riggs, A.D., 1996 Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.
^ Epigenetics
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^ ^a ^b Li, E; Bestor TH and Jaenisch R (June 1992). “Targeted mutation of the DNA methyltransferase gene results in embryonic lethality”. Cell 69 (6): 915–926. doi:10.1016/0092-8674(92)90611-F. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4D57093-1R&_coverDate=06%2F12%2F1992&_alid=515191593&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=7051&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=19d33f62482a44052266e684682a06da.
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^ Mark Ptashne, 2007. On the use of the word ‘epigenetic’. Current Biology, 17(7):R233-R236. doi:10.1016/j.cub.2007.02.030
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^ B.S. Cox (1965). “[PSI], a cytoplasmic suppressor of super-suppression in yeast”. Heredity 20: 505–521. doi:10.1038/hdy.1965.65.
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^ Jablonka, Eva; Gal Raz (June 2009). “Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution”. The Quarterly Review of Biology 84 (2): 131–176. doi:10.1086/598822. http://www.journals.uchicago.edu/doi/abs/10.1086/598822.
^ A.J. Wood and A.J. Oakey (2006). “Genomic imprinting in mammals: Emerging themes and established theories”. PLOS Genetics 2 (11): 1677–1685. doi:10.1371/journal.pgen.0020147. available online
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^ http://www.pbs.org/wgbh/nova/transcripts/3413_genes.html
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^ ^a ^b Tost J (editor). (2008). Epigenetics. Caister Academic Press. ISBN 978-1-904455-23-3 . ISBN 1904455239. http://www.horizonpress.com/epi.