Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency

Abstract

Summary The cellular transcriptional coactivator HCF-1 is required for initiation of herpes simplex virus (HSV) lytic infection and for reactivation from latency in sensory neurons. HCF-1 stabilizes the viral Immediate Early (IE) genes enhancer complex and mediates chromatin transitions to promote IE transcription initiation. In infected cells, HCF-1 was also found to be associated with a network of transcription elongation components including the Super Elongation Complex (SEC). IE genes exhibit characteristics of genes controlled by transcriptional elongation and the SEC-P-TEFb complex is specifically required to drive the levels of productive IE mRNAs. Significantly, compounds that enhance the levels of SEC-P-TEFb also potently stimulated HSV reactivation from latency both in a sensory ganglia model system and in vivo. Thus, transcriptional elongation of HSV IE genes is a key limiting parameter governing both the initiation of HSV infection and reactivation of latent genomes.

CDK9: a signaling hub for transcriptional control

“…Indeed, malfunction of CDK9 activity can promote the development of several diseases including cardiac hypertrophy and leukemia [105,106,115,116]. Furthermore, viruses co-opt transcription elongation complexes to transcribe their genomes and induce a permissive environment for their own replication, thereby causing disease [8,25,117].…”

Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1

“…Having defined HCFC1 as a likely nuclear target of HSP90 in humans, we revisited the TCGA expression data to ask whether the components of the HCFC1 complex are co-expressed with HSP90 in cancers. We used the HCFC1 interactome that we manually curated by combining information from published data (Ajuh et al, 2000;Alfonso-Dunn et al, 2017;Deplus et al, 2013;Liu et al, 2010;Michaud et al, 2013;Parker et al, 2014;Yu et al, 2010; Table S8) and found that HSP90 expression is highly correlated with the expression of HCFC1 interactors in most cancer types ( Figures 4C and S4F). We then analyzed the normalized RNA expression data of individual genes in primary tumors compared to corresponding normal tissues ( Figure S5).…”

Strength in diversity: Understanding the pathways to herpes simplex virus reactivation

“…Recent results suggest that inhibition of BET domain proteins enhances HSV reactivation following explant, indicating that formation of the RNA-polymerase super-elongation complex may promote reactivation (Alfonso-Dunn et al, 2017). In unpublished studies, we have also found that BET-domain inhibitors are sufficient to trigger robust reactivation in human differentiated and primary neurons.…”

“…A component of the repressive PRC1 complex, which is a histone reader often found enriched at sites of cellular H3K27me3, is present at very low levels, if at all, on the latent viral genome (Cliffe et al, 2012; Kwiatkowski et al, 2009). Furthermore, a recent study by Alfonso-Dunn et al (2017) suggests that activation of the super-elongation complex by treatment with BET domain inhibitors enhances reactivation ex vivo , implicating RNA polymerase II promoter-proximal pausing as a rate-limiting step in HSV reactivation. Whether this is due to ‘poised’ RNA polymerase II on the latent viral genome clearly deserves more investigation.…”