By the age of 40 most of us will be infected with human cytomegalovirus (hCMV), which is a human herpes virus. Pretty scary, eh? But fear not, hCMV infections are usually harmless. However, it still posses a significant public health risk as the virus remains the leading infectious cause of birth defects and a serious concern in immune-suppressed patients (including transplant recipients). The double-stranded DNA genomes of hCMV (and other herpesviruses) do not carry histones when on their own (aka encapsidated). But surprisingly, upon release into cell nuclei, hCMV DNA associates with host-derived histones. Given these profound health implications, researchers from Israel, USA and Germany, funded by the Human Frontier Science Program, have formed a collaboration to learn more.

Their previous work has suggested that (canonical) nucleosomes form on nuclear hCMV genomes. Progression through the viral transcriptional program concurs with changes in post-translational histone modifications, as analyzed at individual viral genomic sites. However, information on the nucleosomal organization and function of hCMV chromatin during infection has been limited, in part because no genome-wide studies were available. For instance, senior author, Institute for Medical Microbiology and Hygiene’s (Regensburg, Germany) Dr. Michael Nevels shares “that it was not known whether the hCMV genome has evolved to contain nucleosome favorable and unfavorable sequences, if the viral DNA forms nucleosomes in an organized fashion, how the virus may control its nucleosome organization, and how nucleosome occupancy may regulate viral transcription.”

To address these important questions, the researchers “generated the first spatial and temporal maps of nucleosome occupancy and (nascent) transcription across entire hCMV genomes. This was done following infection of human primary fibroblasts with wild-type viruses and mutants deficient for expression of the viral major immediate-early (IE) 1 protein. IE1 is a chromatin-associated key viral transcriptional regulator and a determinant of hCMV pathogenicity”. Now, with all that said, here’s what they found:

Throughout productive infection nucleosomes are associated with nuclear hCMV DNA in a non-random and highly predictable fashion.

Early nucleosome occupancy is mostly instructed by the viral DNA sequence.

However, nucleosomes undergo massive reorganization as infection proceeds to the late phase, and they eventually form patterns largely determined by non-genetic factors including the IE1 protein.

Notably, IE1 appears to control both the overall nucleosome load and the temporal rearrangements in hCMV chromatin.

They also show that some of the IE1-dependent changes in viral nucleosome occupancy and transcription inversely correlate.

These results suggest that, despite not carrying histones when encapsidated, hCMV genomes encode their own nucleosome organization as well as nucleosome reorganizing mechanisms in order to function properly within the chromatin environment of their host. Dr. Nevels concludes, “Our work puts epigenome research into the context of a common infection and thereby advances our limited knowledge of the epigenetic processes underlying viral disease.”

Get yourself checked out over at PNAS, July 2013