Is epigenetics new? Not to a "smart" influenza virus!

I was browsing the latest papers on Science when I read:

"By mimicking epigenetic regulation in human cells, one flu strain suppresses the expression of antiviral genes [1]."

Wow. Epigenetics and viruses? I had to read that paper!

I've discussed many times how gene expression in cells can be altered through epigenetic changes. The figure below, also taken from [1], shows one of the most common mechanisms by which cells alter gene expression: inside the nucleus, DNA is wound around proteins called histones. The addition of a methyl group (shown in blue in panel b), can alter the transcription of the gene.

In the figure, H3 represents the histone tail. This tail has two amino acids, lysine and arginine, which can be modified in a way that alters the interaction between DNA and the histones. These cause changes in the topology of the chromatin (the way the DNA is packaged inside the nucleus), allowing for certain regions rather than others to be accessed for transcription. If I just gave you a headache, think of chromatin as a tight yarn and you want to poke your finger inside to reach certain threads. The histone tail is like a "lever" that you can use to gain or lose access to the inner parts of the yarn. That's how the cell activates or deactivates genes.

"The ability of histone tails to guide gene function indicates the possibility of targeted control of gene expression by artificial or naturally occurring molecules that can structurally and/or functionally mimic the histone tail [2]."

The influenza A H3N2 subtype has a protein, NS1, that is not vital to viral reproduction but is known to suppress the host's response to the viral infection. In fact, without NS1, the viral infection is significantly mitigated. In a recent Nature paper, Marazzi et al. [2] found that NS1 carries a sequence that resembles the histone H3 tail. This mimicry supports viral infection by halting the transcription of genes essential to counteract the infection.

"We have shown that H3N2 influenza A virus interferes with host gene expression by exploiting the very basic principles of the epigenetic control of gene regulation. By mimicking the histone H3K4 sequence, which has a key role in positive regulation of gene transcription, the influenza virus gains access to histone-interacting transcriptional regulators that govern inducible antiviral gene expression."

Of course, these findings are very intriguing and they raise the question of whether this mechanism is novel to the H3N2 strain or not, and, also, what would happen if a particularly virulent strain like the avian flu would suddenly develop this mechanism as well. At the same time, this opens up new research on ways to attenuate viral infections by targeting the NS1 protein.

[1] Krasnoselsky, A., & Katze, M. (2012). Virology: Influenza's tale of tails Nature DOI: 10.1038/nature11034

[2] Marazzi, I., Ho, J., Kim, J., Manicassamy, B., Dewell, S., Albrecht, R., Seibert, C., Schaefer, U., Jeffrey, K., Prinjha, R., Lee, K., García-Sastre, A., Roeder, R., & Tarakhovsky, A. (2012). Suppression of the antiviral response by an influenza histone mimic Nature, 483 (7390), 428-433 DOI: 10.1038/nature10892