When DNA Is Not Enough: New Research Suggests Epigenetic Factors Play an Important Role in the High Mortality Rate of the Devi Facial Tumor Disease

tazThe 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. Continue reading

Histones and Histone Deacetylases

Epigenetics is an increasingly big deal in biological discovery. We are regularly reading about the influence of actions peripheral to DNA in regulating DNA transcription and translation. We are learning that mice may fear what grandparent mice feared (Kelly’s blog ), due to heritable changes in DNA. In term of one of several mechanisms of epigenetic change, we are learning much about histone deacetylases and their role in gene regulation, as well as disease (Isobel’s blog ). In this blog, let’s take a step back and look at histones, and how they are influenced by acetylation/deacetylation.

The Role of Histones
Histones are proteins found in the nucleus of eukaryotic cells, where they package DNA into nucleosomes. Histones make up the main protein component of chromatin, acting as spool-like structures around which DNA wraps.

There are five major histone classes,three of these are core histones, the other two are called linker histones. Core histones comprise the core of the nucleosome, around which DNA is wrapped, while the linker histones bind at the entrance and exit sites of the DNA, so as to lock it into place. The linker histones also enable a higher order of structure. If you hold both ends of a rubber band, and twist one end, you’ll see that the rubber band twists and folds over itself; the end being held steady enables this twisting and folding: this is how the linker histones work. Histone-DNA structure is frequently represented as a beaded chain-type image (see figure).

DNA wrapping around histones in a bead and chain-like fashion.

DNA wrapping around histones in a bead and chain-like fashion.

Histone and DNA: Charged Interactions
Histone tails normally carry a positive charge due to amine groups present on their lysines and arginines. This positive charge is the means by which histone tails interact with and bind to the negatively-charged phosphate groups on the DNA backbone.

Histones are subject to post-translational modifications, primarily on their N-terminal tails, by enzymes. Such modifications include methylation, citrullination, acetylation, phosphorylation, SUMOylation, ubiquitination, and ADP-ribosylation. Such modifications can affect histone function in gene regulation. Acetylation is one of the most common post-translational modifications of histones (1). Continue reading