title: The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection.
abstract: Originally identified as an essential component of the herpes simplex virus immediate early (IE) gene enhancer complex, the transcriptional coactivator host cell factor-1 (HCF-1) has been implicated in a broad range of cellular regulatory circuits. The protein mediates activation through multiple interactions with transcriptional activators, coactivators, and chromatin remodeling complexes. However, the mechanisms involved in HCF-1-dependent transcriptional stimulation were undefined. By using a minimal HCF-1-dependent promoter and a model activator, the varicella zoster IE62 protein, it was determined that HCF-1 was not required for the assembly of the RNAPII basal complex, which depended solely on IE62 in conjunction with the cellular factor Sp1. In contrast, HCF-1 was required for recruitment of the histone methyltransferases Set1 and MLL1 (mixed-lineage leukemia 1), leading to histone H3K4 trimethylation and transcriptional activation. Similarly, in a varicella zoster virus lytic infection, HCF-1, Set1, and MLL1 were recruited to the viral genomic IE promoter, suggesting an essential role for HCF-1 in chromatin modification and remodeling during initiation of lytic infection. The results indicate that one biological rationale for the incorporation of the viral IE activators in the viral particle is to recruit HCF-1/histone methyltransferase complexes and promote assembly of the viral IE gene promoters into transcriptionally active chromatin. These studies also contribute to the model whereby the induced nuclear transport of HCF-1 in sensory neurons may be critical to the reactivation of latent herpesviruses by promoting the activation of chromatin modifications.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4-131, 4 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Narayanan
authors.forename: William T
authors.initials: WT
authors.lastname: Ruyechan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kristie
mesh_terms: D021581:Active Transport, Cell Nucleus; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D006367:HeLa Cells; D006561:Herpes Simplex / Q000209:etiology*; D056488:Histone Chaperones; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D051863:Host Cell Factor C1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins; D008745:Methylation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000235:genetics* / Q000472:pathogenicity*; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014759:Viral Envelope Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; D051863:Host Cell Factor C1; C074221:IE62 protein, Human herpesvirus 3; D017874:Immediate-Early Proteins; C497422:KMT2A protein, human; C513473:SET protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014759:Viral Envelope Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase