The Devil Facial Tumor Disease (DFTD) is a contagious cancer in Tasmanian Devils that is threatening the species with extinction. This disease is spread from individual to individual and has a 100% mortality rate. It is so deadly because, although the DFTF cells should be attached and killed by the host devil’s immune system, for some reason they are not—and no one is sure why. A study published in PNAS in March of last year (1) showed that DFTD cells don’t express surface MHC molecules. MHC class I and class II molecules are crucial for proper immune response, and their absence on the cell surface could explain why the DFTD cells do not stimulate an immune response.
The authors found that the loss of MHC expression is maintained as the cells divide, and is not a result of structural mutations in the genes responsible for MHC expression. Instead the authors found that this down regulation was the result of regulatory changes including epigenetic modifications to histones.
Epigenetics is a relatively new term in biology. Whereas genetics is the study of the mechanism of inherited traits and changes that are a direct result of the genes—the DNA sequences, epigenetics is the study of heritable changes that are not due to changes in DNA sequence.
In the case of DFTD, the authors found nothing wrong with the genes involved in MHC expression; instead they found that suppression of these genes was a related to the acetylation state of histones which changed the chromatin structure within these regulatory regions. First, they demonstrated that the genes involved in MHC expression were intact, and that they could isolate full length transcripts from DFTD cell lines. Further, they showed that these transcripts were capable of translation and forming functional molecules. This showed that structural mutations in the genes did not explain the MHC expression down regulation. Next they treated DFTD cells with histone deacetylase inhibitor trichostatin A (TSA). TSA-treated TFTD cells showed an increase of MHC class I protein (as detected by Western blot).
TSA treatment only partially restored gene expression of the MHC-associated genes. In particular, the MHC class II transactivator, CIITA, was not up regulated following TSA treatment. CIITA is a transcription factor that binds in the promoter elements of the MHC class I, MHC class II and ß2-m genes, inducing or up-regulating expression. Exposure to the cytokine, IFN-Γ, is known to result in expression of CIITA. The authors found that expression of CIITA was increased when the DFTD cells were treated with the cytokine IFN-Γ. Along with helping transcription factors bind to promoters for MHC class I, class II and ß2-m, CIITA also has acetyltransferase activity that relaxes chromatin structure and allows transcription factors access to the DNA. Although inhibition of histone deacetylation with TSA resulted in some increase in the MHC expression, the authors speculated that CIITA might be needed for full acetylation and gene expression.
It is very possible that this work only shows a piece of the puzzle of what causes the MHC down regulation in DFTD, but by demonstrating that the loss of expression occurs as a result of regulatory changes and not structural mutations, scientists now have a path to pursue in designing a effective vaccine against DFTD. By exposing animals to engineered DFTD cells that have been treated to up-regulate MHC expression, they will have the opportunity to generate an immune response that could carry over when they are exposed to the wild-type disease. Given how fast this disease is killing off the Tasmanian Devil population, an approach like this might be their best hope.
- Siddle, H.V. et al. (2013) Reversible epigenetic down-regulation of MHC molecules by devil facial tumor disease illustrates immune escape by a contagious cancer. Natl Acad. Sci. USA. 110, 5103–8.