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How can a single-celled organism like the ciliated protozoan Tetrahymena provide insight into epigenetics?
TAVERNA: There is a common misconception that epigenetics isn't at play in single-celled organisms but some of the first evidence for non-Mendelian inheritance was in single-celled ciliated protozoa. Tetrahymena, in particular, turns out to be well suited for epigenetics studies. It maintains two separate nuclei at the same time: one contains the germline genome, a full copy of its DNA that gets passed down to the next generation, and the other contains the somatic genome, the DNA that gets transcribed.
When Tetrahymena are “born,” they inherit germline DNA from their parents, but the somatic nucleus then differentiates from a germline nucleus in an epigenetic process that is directed in part by the parent’s somatic genomes. To do this, the somatic genome goes through a period of heterochromatin formation and gene silencing during which they get rid of DNA they don’t express. We can synchronize the life cycle of Tetrahymena so that they undergo this process of gene silencing at the same time and by doing this, we have a real chance at figuring out how the gene silencing pathway works through biochemical or other approaches.
How does this relate to cancer?
TAVERNA: We know that some cancer cells grow out of control due to shutting off or silencing of genes that normally would prevent these cells from going awry. How this happens is of obvious interest and Tetrahymena comes in as a useful genetically tractable model to study this process.
But it’s a big leap between Tetrahymena and human beings.
TAVERNA: Well, we know that genes can be silenced by the addition of a methyl group to a specific location on a histone protein. Conveniently, histones are some of the most highly conserved proteins across all eukaryotes. Also, the machinery that puts methyl groups on histones is very highly conserved as well; it is so recognizable that you can easily pick it out of a lineup. So if we develop drugs that affect histone methylation in Tetrahymena, it is likely that these same drugs would be effective in higher organisms, including humans.
Is there any evidence that drugs work the same way in Tetrahymena and humans?
TAVERNA: There is a first-generation anticancer drug called SAHA for suberoylanilide hydroxamic acid that inhibits histone deacetylases and leads to increased acetylation of histone protein tails. Acetylation of these tails is a signal for gene transcription and may prevent certain tumor-suppression genes from being silenced. Certain types of cancer respond very well to SAHA; it’s almost like the tumors melt away. However, aside from the observed increase in histone acetylation we don’t understand the mechanism of action. Interestingly, histone deacetylase inhibitors also increase histone acetylation in Tetrahymena, indicating there may be mechanistic overlaps in how diverse organisms use epigenetics to control gene expression.