Medicinal Food Meets Epigenetics

E pigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. Seminal work in the field was conducted during the 1950s by Barbara McClintock, who while working at Cold Spring Harbor Laboratory revealed that there were heritable yet reversible modifications in human gene expression that occurred over generations. In 1975 Arthur Riggs and Robin Holliday separately reported that DNA modification was mediated by cytosine methylation. DNA methylation represented an entirely new mechanism for the regulation of gene expression. A second fundamental observation was made in 1964 by Vincent Allfrey at Rockefeller University, who posited that the reversible acetylation of nuclear histone proteins could also regulate transcription. However, it wasn't until 1996, when C. David Allis's laboratory cloned the histone acetyltransferase (HAT1) and confirmed its homology with yeast Gcn5 almost simultaneously with Schreiber's laboratory at Harvard University describing the first histone deacetylase (HDAC), that Allfrey's original observation was confirmed and the field of epigenetics was born.

We now recognize that gene expression only starts at the level of DNA. To achieve function, proteins must survive a myriad of regulatory hurdles that begin with DNA methylation and histone acetylation. They must then circumvent down-regulation with small interfering RNA and successfully negotiate chaperone interactions before they can assume their quaternary structure under the further influence of phosphorylation, glycosylation, and glutathionylation. It is increasingly evident that the publication of the final human genome map in 2003 marked not the end but the beginning of our quest to understand the complexities of human biology.

In the current issue of the Journal of Medicinal Food, Si Yong Park and collaborators report the activity of grape seed extract (GSE) as a regulator of histone acetylation, providing a new and exciting possible insight into the activity of the polyphenols found in grape products. ¹ These investigators used prostate cancer to examine the effects of GSE on androgen receptor (AR)-regulated genes. The effect of a methanol extract of grape seeds on HAT activity was measured by autoradiography. RNA and protein expressions were then measured and compared with cell viability and cell cycle analysis. They found that HAT activity is inhibited by GSE and that this inhibition results in the down-regulation of several genes under AR control. While HDAC activity appeared unaffected, HAT activity was inhibited up to 80%, resulting in the repression of AR-mediated transcription in the LnCAP human prostate cancer cell line model. Cell viability assessed by tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reduction was reduced by 18%, associated with a shift to sub-G₁ and the induction of apoptosis. The authors' findings indicate that among the known anti-inflammatory and antioxidant properties of GSE we must now include HAT inhibitory properties as important mediators of GSE's biological actions.

What is most exciting about this line of research is that it forces us to confront the reality that human biology is not linear. Our attempts to capture biological phenomena in silico, culminating in the human genome project, are continually thwarted by the complexities, redundancies, and promiscuities of human physiology. The simplistic view of antioxidants as chemical reactants with free radicals at the level of stoichiometry was dealt a deathblow by the description of keap-1 and nrf2 that defined critical gene regulatory roles for these important nutrients. As the authors of this article point out, many substances—including curcumin and diallyl sulfide—may, in part, provide their salutary benefits through the histone acetylation/deacetylation pathways. The findings in this article, in keeping with the growing field of epigenetics, force us to once again to confront the humbling recognition that genotype ≠ phenotype.