Dengue versus the epigenome

Dengue virus (DENV) particles. Does dengue interact with the host epigenome? And, why?

Epigenetic modification of chromosomal structure has the ability to rapidly and stably alter gene expression and function within cells, tissues and whole organisms. And, changes have been found to induce a number of diseases in humans, such as cancer and others.

The ability of infecting viruses to influence this process has now been realized with a number of large DNA viruses being shown to take advantage of host epigenetic modifications, including: the histone proteins that are necessary for the structure and modulation of chromatin.

But what hasn't been seen is whether RNA viruses, which replicate within the cytoplasm are able to at least interact with the host chromosome structures. And, more importantly, why would they do so? Researchers have just published evidence suggesting that dengue virus interacts directly with host histone proteins and requires such activity for replication (see PLoS paper here). The reasons why are not understood.

DENV-C specific histone binding (binds to H2A, B, 3 and 4) but not GFP. Does this has an affect on host function?

Dengue Virus (DENV) is a small, single-stranded, positive-sensed RNA virus and belongs within the Flavivirus genus, alongside yellow fever virus and west Nile fever virus. It is spread between humans via the bite of the female Aedes mosquito and can lead to the development of very high fever (41 degrees Celsius), headache and in some cases, a lethal hemorrhagic fever.

It is estimated that two-fifths of the worlds' population are at risk of DENV infection and it is endemic in over 100 countries within tropical or sub-tropical climates. There is currently no clinically proven treatment for dengue fever nor are there any vaccines available, making any research into the basic biology of the virus all the more important.

Using a 'tagged' protein, this group showed that a recombinant DENV C protein (capsid protein forming the outer layers of the virus particle - yellow in the above picture) interacts with the four core histones, H2A, H2B, H3 and H4 found within the nucleus of huh-7 cells, a human hepatocellular carcinoma cell line used a lot in DENV research. See the figure above for the specific binding. DENV is known to infect human liver cells, especially in fatal cases.

GFP-tagged DENV-C co-localizes with huh-7 nuclear and cytoplasmic histones (H2A and H2B)

When over-expressed within these cells, a GFP-tagged C localised to the same areas of the nucleus as each of the histones did and this was extended to DENV-infected cells (see above). C also interacted with the histones while in the cytoplasm as well. In vitro C and histones formed dimers together in the absence of nucleic acids and it was subsequently shown to bind DNA with - or without - histone proteins. See below.
 
This interaction was shown to disrupt the normal oligomerization of histones but not that of histone-DNA binding. Infection up-regulated the expression of the core histones and was essential for normal DENV replication.

DENV-C binds to huh-7 H2A, B, 3 and 4 and causes formation of oligomers (the bands higher up on the gel - compared to lower and smaller bands).

The physical basis of this interaction is currently not understood but is believed to result from the structural similarities between the histones and DENV-C. A common folding pattern - important for oligermization - is shared by both and the authors state they are in the process of crystallizing the two together. The biological significance of this observation was not really addressed here, apart from the fact that histones were required for DENV replication (see graph below). The authors hypothesize the reasons as to why DENV might need this process, but provide no evidence to back it up.

DENV replication requires H2A and H3 proteins. Shown here by siRNA knockowns of the two (columns 1 - 4) when compared to non-specific controls (5 and 6).

It would be interesting to see if this interaction applied to other human cells, including primary cell lines and maybe in vivo. And, if it extended to mosquito cells as well? But, where in the genome does DENV-C bind? Is it specific or more general? What is the basis of the requirement for these histone proteins? Finally, is it possible to inhibit this relationship to develop new anti-DENV therapies.


Colpitts, T., Barthel, S., Wang, P., & Fikrig, E. (2011). Dengue Virus Capsid Protein Binds Core Histones and Inhibits Nucleosome Formation in Human Liver Cells PLoS ONE, 6 (9) DOI: 10.1371/journal.pone.0024365