Control of cytomegalovirus lytic gene expression by histone acetylation.
Permissiveness for human cytomegalovirus (HCMV) infection is dependent on the state of cellular differentiation and has been linked to repression of the viral major immediate early promoter (MIEP). We have used conditionally permissive cells to analyze differential regulation of the MIEP and possible mechanisms involved in latency. Our data suggest that histone deacetylases (HDACs) are involved in repression of the MIEP in non-permissive cells as inhibition of HDACs induces viral permissiveness and increases MIEP activity. Non-permissive cells contain the class I HDAC, HDAC3; super-expression of HDAC3 in normally permissive cells reduces infection and MIEP activity. We further show that the MIEP associates with acetylated histones in permissive cells, and that in peripheral blood monocytes the MIEP associates with heterochromatin protein 1 (HP1), a chromosomal protein implicated in gene silencing. As monocytes are believed to be a site of viral latency in HCMV carriers and reactivated virus is only observed upon differentiation into macrophages, we propose that chromatin remodeling of the MIEP following cellular differentiation could potentially play a role in reactivation of latent HCMV.
Murphy
Jane C
JC
Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK. jcm25@mole.bio.cam.ac.uk
Fischle
Wolfgang
W
Verdin
Eric
E
Sinclair
John H
JH
D000107:Acetylation; D002454:Cell Differentiation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000502:physiology*; D017781:Genes, Immediate-Early; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000821:virology; D008957:Models, Genetic; D009000:Monocytes / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D018243:Teratocarcinoma / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000821:virology; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014775:Virus Activation / Q000235:genetics; D017735:Virus Latency / Q000235:genetics; D000099186:Histone Deacetylase 3
D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D017874:Immediate-Early Proteins; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D000099186:Histone Deacetylase 3; C012589:trichostatin A