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Tapioca – A Novel Platform for Prediction Of Protein-Protein Interaction Dynamics Identifies NUCKS1 as a Broad-Spectrum Herpesvirus Proviral Factor

ABSTRACT: Understanding protein-protein interaction (PPI) network dynamics is key to understanding nominal and perturbed cell states. Here, we develop a new machine learning framework called Tapioca that allows for the study of PPIs in dynamics contexts at a global scale in ex/in vivo conditions. Furthermore, we optimized the thermal denaturation and lysis conditions used in the thermal proximity coaggregation (TPCA) methodology, one of the types of data Tapioca can use to make predictions. Using this optimized protocol and Tapioca, we investigated the temporal dynamics of reactivation from latency of the oncogenic gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV), identifying the host protein NUCKS1 as a factor promoting KSHV genome replication during lytic infection. Integrating this dataset with published TPCA datasets from the alphaherpesvirus herpes simplex virus type-1 (HSV-1) and the betaherpesvirus human cytomegalovirus (HCMV), we determined NUCKS1 to have a proviral role across all three herpesvirus subfamilies.

ORGANISM(S): Homo Sapiens Human Herpesvirus 8 Strain Gk18

SUBMITTER: Matthew Tyl

PROVIDER: PXD041269 | panorama | Sat Dec 02 00:00:00 GMT 2023

REPOSITORIES: PanoramaPublic

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Project description:Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral >230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes defcient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-defcient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function. [i] H3 ChIP-chip measurements of WT human cytomegalovirus (strain TB40E) following infection of MRC-5 cells. WT 8 hours postinfection, with corresponding mock IgG input control: 3 replicates; WT virus, 48 hours postinfection with corresponding mock IgG input contro: 3 replicates. [ii] MNase-chip measurements of WT and dlIE1 human cytomegalovirus nucleosomes following infection of MRC-5 cells. WT 8 hours postinfection, with corresponding sonicated DNA input control: 6 replicates; WT virus 48 hours postinfection, with corresponding sonicated DNA input control: 6 replicates; WT 96 hours postinfection, with corresponding sonicated DNA input control: 2 replicates; dlIE1 virus 8 hours postinfection, with corresponding sonicated DNA input control: 2 replicates; dlIE1 virus 96 hours postinfection, with corresponding sonicated DNA input control: 2 replicates. [iii] Total and nascent RNA measurements of WT and dlIE1 human cytomegalovirus transcripts following infection of MRC-5 cells. WT 8 hours postinfection: 2 replicates; WT virus 96 hours postinfection: 2 replicates; dlIE1 8 hours postinfection: 2 replicates; dlIE1 virus 96 hours postinfection: 2 replicates; sonicated DNA input control: 10 replicates.

Dataset Information

Tapioca – A Novel Platform for Prediction Of Protein-Protein Interaction Dynamics Identifies NUCKS1 as a Broad-Spectrum Herpesvirus Proviral Factor

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