Acetylated microtubules refine cytomegalovirus interactions with and remodeling of host chromatin [CUT&Run]

Human cytomegalovirus extensively alters nuclear organization and the cellular transcriptome, yet our understanding of these events remains relatively limited. Here, chromatin conformation capture reveals that cytomegalovirus dramatically alters chromosome organization at both large-scale and local compartment levels. Nascent transcriptomics further reveals the extent to which transcriptional changes correlate with compartment changes, while also uncovering infection-induced read-in and read-through events that result in the expression of normally repressed neuronal genes in infected fibroblasts. Moreover, we find that viral genomes preferentially localize to the most abundant and euchromatic compartments of the host, further dysregulating transcription of subsets of host genes. Finally, we show that microtubule-derived forces on the nucleus regulate viral interactions with host chromatin as well as local compartment interactions, which in turn influences infection-induced transcriptional reprogramming. Combined, our findings reveal the extent to which HCMV alters chromatin organization and transcriptional activity, along with the contribution of microtubules to these processes. Overall design: CUT&RUN profiling of H3K9me3 and H3K4me3 in mock fibroblasts and HCMV infected conditions (MOI5) at 96hrs