Chromatin-mediated regulation of cytomegalovirus gene expression.
Following primary infection, whether Human cytomegalovirus (HCMV) enters either the latent or lytic lifecycle is dependent on the phenotype of the cell type infected. Multiple cell types are permissive for lytic infection with HCMV whereas, in contrast, well characterized sites of latency are restricted to a very specific population of CD34+ cells resident in the bone marrow and the immature myeloid cells they give rise to. It is becoming increasingly clear that one of the mechanisms that promote HCMV latency involves the recruitment of histone proteins to the major immediate early promoter (MIEP) which are subject to post-translational modifications that promote a transcriptionally inactive state. Integral to this, is the role of cellular transcriptional repressors that interact with histone modifying enzymes that promote and maintain this repressed state during latency. Crucially, the chromatin associated with the MIEP is dynamically regulated-myeloid cell differentiation triggers the acetylation of histones bound to the MIEP which is concomitant with the reactivation of IE gene expression and re-entry into lytic infection. Interestingly, this dynamic regulation of the MIEP by chromatin structure in latency extends not only into lytic infection but also for the regulation of multiple viral promoters in all phases of infection. HCMV lytic infection is characterised by a timely and co-ordinated pattern of gene expression that now has been shown to correlate with active post-translational modification of the histones associated with early and late promoters. These effects are mediated by the major IE products (IE72 and IE86) which physically and functionally interact with histone modifying enzymes resulting in the efficient activation of viral gene expression. Thus chromatin appears to play an important role in gene regulation in all phases of infection. Furthermore, these studies are highly suggestive that an intrinsic cellular anti-viral response to incoming viral genomes is to promote chromatinisation into a transcriptionally repressed state which the virus must overcome to establish a lytic infection. What is becoming evident is that chromatin structure is becoming as increasingly important for the regulation of viral gene expression as it is for cellular gene expression and thus understanding the mechanisms employed by HCMV to modulate chromatin function could have broader implications on our understanding of the control of gene expression in general.
Reeves
Matthew B
MB
Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. mbr23@cam.ac.uk
D000107:Acetylation; D002843:Chromatin / Q000235:genetics / Q000821:virology*; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000821:virology; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D015534:Trans-Activators / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D015534:Trans-Activators