Microtubule mechanotransduction refines cytomegalovirus interactions with and remodeling of host chromatin.

Human cytomegalovirus extensively alters nuclear organization and the cellular transcriptome, yet understanding of these genome-wide events remains relatively limited. Here, chromatin conformation capture (Hi-C) revealed how cytomegalovirus alters chromosome organization at both large- and small-scales. Nascent transcriptomics further revealed how transcriptional changes correlate with genomic reorganization, while also uncovering infection-induced transcriptional dysregulation that contributes to the induction of neuronal gene signatures in infected fibroblasts. Combining Hi-C and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) we find that viral genomes preferentially localize to highly euchromatic compartments, further dysregulating transcription of host genes. Finally, RNAi-mediated depletion of two key effectors of microtubule-based forces that are exerted on the nucleus provides insights into their diverging roles in regulating compartment-scale contacts and viral genomic interactions with host chromatin. Combined, we reveal the extent to which HCMV interacts with and alters host chromatin and transcription, and the influence of microtubule mechanotransduction on these processes.