A Role for the Nucleosome Assembly Proteins TAF-Iβ and NAP1 in the Activation of BZLF1 Expression and Epstein-Barr Virus Reactivation

Abstract

The reactivation of Epstein-Barr virus (EBV) from latent to lytic infection begins with the expression of the viral BZLF1 gene, leading to a subsequent cascade of viral gene expression and amplification of the EBV genome. Using RNA interference, we show that nucleosome assembly proteins NAP1 and TAF-I positively contribute to EBV reactivation in epithelial cells through the induction of BZLF1 expression. In addition, overexpression of NAP1 or the β isoform of TAF-I (TAF-Iβ) in AGS cells latently infected with EBV was sufficient to induce BZLF1 expression. Chromatin immunoprecipitation experiments performed in AGS-EBV cells showed that TAF-I associated with the BZLF1 promoter upon lytic induction and affected local histone modifications by increasing H3K4 dimethylation and H4K8 acetylation. MLL1, the host protein known to dimethylate H3K4, was found to associate with the BZLF1 promoter upon lytic induction in a TAF-I-dependent manner, and MLL1 depletion decreased BZLF1 expression, confirming its contribution to lytic reactivation. The results indicate that TAF-Iβ promotes BZLF1 expression and subsequent lytic infection by affecting chromatin at the BZLF1 promoter.

Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis

“…The local acetylation state of histones H3 and H4 around Zp and Rp, such as histone H3 Lys27 acetylation (H3K27ac), H3K9ac, and H4K8ac, help to establish the open chromatin configuration so as to allow access of transcription factors, followed by transcription of the BZLF1 and BRLF1 genes 46-48. In contrast, the methylation modifications of histones were suggested to be marks of heterochromatin formation and transcriptional repression.…”

Distinct roles of the histone chaperones NAP1 and NRP and the chromatin‐remodeling factor INO80 in somatic homologous recombination in Arabidopsis thaliana

“…Within the NAP1 family, NRP1 and NRP2 are grouped closely together with the yeast Vps75 and the metazoan oncoprotein SET/TAF-I/I 2 PP2A / INHAT, forming a separate phylogenetic clade (Dong et al, 2003). Vps75 and SET/TAF-I/I 2 PP2A /INHAT have threedimensional structures largely similar to NAP1 (Muto et al, 2007;Tang et al, 2008) and also share many similar biochemical activities with NAP1 in nucleosome assembly/disassembly, DNA replication and transcription (Selth et al, 2009;Kato et al, 2011;Mansouri et al, 2013;Xue et al, 2013). Meanwhile, distinct activities of Vps75 and SET/TAF-I/I 2 PP2A /INHAT have also been reported, e.g.…”

Alterations in Acetylation of Histone H4 Lysine 8 and Trimethylation of Lysine 20 Associated with Lytic Gene Promoters during Kaposi��s Sarcoma-Associated Herpesvirus Reactivation

“…In EBV-infected cells, H4K8 acetylation occurs when TAF-1β, which is associated with acetylation activity, binds to the p300/CBP complex containing a histone acetyltransferase domain. Additional experiments are essential to establish whether TAF-1β influences H4K8ac and the effects of other coactivators, such as p300/CPB, in KSHV-infected cells [28,38,39]. Suppressor of variegation 420h (Suv420h) containing a SET domain has been identified as an H4K20me3 methyltransferase.…”

“…Histone methylation contributes to both transcriptional activation and inactivation. For instance, H3K4me, H3K36me, and H3K79me have been identified as activation markers at activated gene regions and H3K9me, H4K20me, and H4K27 as repressive markers at inactivated gene regions [27][28][29].…”

“…In EBV displaying high similarity to KSHV, the IF protein BZLF1 plays a crucial role in viral reactivation. H3K4me3 and H4K8ac have been identified as activation markers at the promoter region of BZLF1 during EBV reactivation, and, conversely, H3K27me and H4K20me3 are reported as negative markers during latency resulting in gene silencing [28,30]. Previous studies on histone modifications in KSHV have mainly been performed on H3, and not H4.…”