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The Coactivator Host Cell Factor-1 Mediates Set1 and MLL1 H3K4 Trimethylation at Herpesvirus Immediate Early Promoters for Initiation of Infection

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The Coactivator Host Cell Factor-1 Mediates Set1 and MLL1 H3K4 Trimethylation at Herpesvirus Immediate Early Promoters for Initiation of Infection The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection Aarthi Narayanan*, William T. Ruyechan†, and Thomas M. Kristie*‡ *Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4-131, 4 Center Drive, Bethesda, MD 20892; and †Department of Microbiology and Immunology, University at Buffalo, State University of New York, 251 Biomedical Research Building, Buffalo, NY 14214 Communicated by Bernard Moss, National Institutes of Health, Bethesda, MD, May 9, 2007 (received for review March 23, 2007) Originally identified as an essential component of the herpes Since its identification as a coactivator for the herpesvirus simplex virus immediate early (IE) gene enhancer complex, the activators, several lines of evidence have indicated that HCF-1 transcriptional coactivator host cell factor-1 (HCF-1) has been also plays a broadly significant role in cellular transcription. The implicated in a broad range of cellular regulatory circuits. The protein (i) is a binding partner and/or coactivator for numerous protein mediates activation through multiple interactions with cellular transcription factors including those of the krupple (Sp1 transcriptional activators, coactivators, and chromatin remodel- and Krox20), Ets (GABP), ATF/CRE (CREB3), and E2F (E2F1 ing complexes. However, the mechanisms involved in HCF-1- and E2F4) families (10–16), (ii) interacts with other coactivators dependent transcriptional stimulation were undefined. By using (PGC and FHL2) (17, 18) where it has been hypothesized to a minimal HCF-1-dependent promoter and a model activator, the mediate coactivator–activator interactions, (iii) is essential for varicella zoster IE62 protein, it was determined that HCF-1 was multiple stages of cell cycle progression (19, 20), and (iv) has not required for the assembly of the RNAPII basal complex, recently been identified as a component of complexes involved which depended solely on IE62 in conjunction with the cellular in chromatin modification and remodeling (21–23). Further- factor Sp1. In contrast, HCF-1 was required for recruitment of the more, expression array studies have identified a wide range of histone methyltransferases Set1 and MLL1 (mixed-lineage target genes whose expression is affected in cells in which the leukemia 1), leading to histone H3K4 trimethylation and tran- nuclear accumulation of HCF-1 has been inhibited (24). How- scriptional activation. Similarly, in a varicella zoster virus lytic ever, although activator partners and target genes have been identified, the biochemical mechanism by which HCF-1 stimu- infection, HCF-1, Set1, and MLL1 were recruited to the viral lates transcription is undefined. genomic IE promoter, suggesting an essential role for HCF-1 in In this study, a model promoter (VZV IE62 promoter) and chromatin modification and remodeling during initiation of lytic activator (VZV IE62) were studied to determine the role of infection. The results indicate that one biological rationale for HCF-1 in recruitment of the general transcription factor com- the incorporation of the viral IE activators in the viral particle is plex and in mediating activating chromatin modifications. The BIOCHEMISTRY to recruit HCF-1/histone methyltransferase complexes and pro- results demonstrate that IE62, in conjunction with the ubiqui- mote assembly of the viral IE gene promoters into transcrip- tous factor Sp1, mediates the assembly of the initiation complex. tionally active chromatin. These studies also contribute to the Promoter occupancy of HCF-1 is not required for this assembly model whereby the induced nuclear transport of HCF-1 in but is essential for transcriptional activation via recruitment of sensory neurons may be critical to the reactivation of latent the H3K4 methyltransferases Set1 and MLL1 (mixed-lineage herpesviruses by promoting the activation of chromatin leukemia 1). Strikingly, Sp1 is required to bridge or stabilize the modifications. interaction of the IE62 activator with the HCF-1 transcriptional coactivator, suggesting that this protein may play a general role chromatin ͉ histone methyltransferase ͉ chromatin modifications ͉ in mediating HCF-1-activator interactions. Finally, the recruit- Sp1 ͉ transcription ment of HCF-1 and the Set1/MLL1 histone methyltransferases (HMTs) to the viral IE promoter during the initiation of he cellular transcriptional coactivator host cell factor-1 infection indicates that chromatin modification and remodeling ␣ T(HCF-1) was originally isolated as a component of the herpes represent critical stages in the activation of -herpesvirus tran- simplex virus (HSV) immediate early (IE) gene enhanceosome scription. The data support the model in which HCF-1- complex containing the cellular POU domain protein Oct-1 and dependent chromatin modulation would play a critical role in the the viral transactivator VP16 (1–6). The protein has been most regulation of the viral lytic and latency reactivation cycle. thoroughly studied in this context where it mediates the VP16 Results transcriptional activation of the viral IE genes (7, 8). In an HCF-1-Dependent Coactivation of IE62 Target Genes. Previously it analogous manner, HCF-1 also mediates the induction of the was demonstrated that HCF-1 was an essential component related varicella zoster virus (VZV) IE genes by the viral transactivators ORF10 and IE62 (8). The transcription of these ␣ -herpesvirus genes is regulated by multiple mechanisms and Author contributions: A.N. and T.M.K. designed research; A.N. performed research; W.T.R. factors via complex combinatorial enhancer-promoter domains. contributed new reagents/analytic tools; A.N. and T.M.K. analyzed data; and A.N. and Strikingly, HCF-1 has been shown to be essential for IE gene T.M.K. wrote the paper. expression, suggesting that it mediates a common rate-limiting The authors declare no conflict of interest. step. Most intriguingly, both HSV and VZV establish latency in Freely available online through the PNAS open access option. the neurons of sensory ganglia. In these cells, HCF-1 is uniquely Abbreviations: HCF-1, host cell factor-1; HSV, herpes simplex virus; IE, immediate early; VZV, sequestered in the cytoplasm of sensory neurons and is rapidly varicella zoster virus; HMT, histone methyltransferase. transported to the nucleus upon stimulation that results in viral ‡To whom correspondence should be addressed. E-mail: thomas࿝[email protected]. reactivation (9). Therefore, whereas the protein is essential for This article contains supporting information online at www.pnas.org/cgi/content/full/ viral lytic replication, it may also be a key component in the 0704351104/DC1. ␣-herpesvirus latency reactivation cycle. © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0704351104 PNAS ͉ June 26, 2007 ͉ vol. 104 ͉ no. 26 ͉ 10835–10840 Downloaded by guest on September 30, 2021 Fig. 2. Recruitment of transfected and endogenous HCF-1 in the presence and absence of IE62. ChIP assays were done 48 h after transfection by using the indicated antibodies or control antibodies (HA, V5, and IgG). The signal intensities were quantitated as described in Materials and Methods and are expressed as a percentage of the extract signal. The data shown are derived from a single ChIP assay but are representative of at least two independent experiments. ϩIE62/ϪIE62 is the fold ratio of the intensities in the presence of IE62 to those in the absence of IE62. (Upper) HeLa cells were transfected with the IE62P-61 reporter plasmid (Reporter), the HA-tagged IE62 expression Fig. 1. HCF-1-dependent coactivation of a minimal IE62 target gene. (A) The plasmid (HA-IE62), and/or the V5-tagged HCF-1 expression plasmid (HCF-1-V5) IE62 promoter–reporters are schematically illustrated, depicting the binding as indicated. (Lower) HeLa cells were transfected with the IE62P-61 reporter sites for various cellular and viral factors. EC represents the VZV IE enhancer plasmid (Reporter) or cotransfected with the pCMV-IE62 expression plasmid. core that assembles the Oct-1, ORF10, and HCF-1 multiprotein complex. GA, Ext, input extract before immunoprecipitation. Sp1, CCAAT, CRE, and IE62 are the putative binding sites for GA-binding protein, Sp1, CCAAT-binding proteins, ATF/CRE factors, and VZV IE62, respec- ϩ tively. Luc, luciferase reporter gene coding region; 1, transcription initiation IE62 Recruitment of the Coactivator HCF-1 to the IE62 Minimal Model site. (B) HeLa cells were transfected with HCF-1 RNAi vector pU6-si-HCF-1 (Si) Promoter. or the control RNAi pU6-si (C). The indicated reporter genes were transfected The HCF-1 dependence of IE62-mediated activation or cotransfected 48 h later with increasing amounts of pCMV-IE62 (0, 50, 100, suggested that IE62 might directly recruit HCF-1 to the mini- and 200 ng). Reporter expression levels were normalized to the activity of the mally responsive promoter target gene. Therefore, HCF-1 pro- control vector (fold expression of reporter relative to control). The data are moter occupancy was determined by ChIP assays in the presence representative of three independent experiments. HCF-1 depletion was de- and absence of IE62. As shown in Fig. 2, both cotransfected termined to be 70% by quantitative Western blot analysis, whereas no effect V5-tagged HCF-1 (Fig. 2 Upper) and endogenous HCF-1 (Fig. on the expression of IE62 in HCF-1-depleted cells was detected. 2 Lower) were recruited
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