Human papillomavirus genomes associate with active host chromatin during persistent viral infection

Area of Science:

• Virology
• Epigenetics
• Cancer Biology

Background:

• Human papillomaviruses (HPVs) establish persistent infections by maintaining their genomes as minichromosomes within host keratinocyte nuclei.
• Understanding the interaction between viral genomes and host chromatin is crucial for elucidating viral persistence and oncogenesis.

Purpose of the Study:

• To investigate the association of HPV31 genomes with host chromatin structures.
• To correlate viral genome association sites with host transcriptional activity and DNA break susceptibility.
• To explore the implications for viral gene expression and HPV-associated cancer development.

Main Methods:

• Employed chromosome conformation capture techniques, specifically HiC and 4C-seq, to map HPV31 genome interactions with host chromatin.
• Integrated data from ATAC-seq (open chromatin) and ChIP-seq (Brd4, H3K27ac for super-enhancers) to define host chromatin features.
• Analyzed correlations with dsDNA break (dsBREAK) datasets and known HPV integration sites in cervical cancers.

Main Results:

• HPV31 genomes preferentially associate with transcriptionally active A compartments, open chromatin regions (ATAC-seq), and super-enhancers (Brd4, H3K27ac).
• Viral genome association sites strongly correlate with common HPV integration sites found in cervical cancers.
• A significant correlation exists between HPV31 genome association sites, transcriptionally active/open chromatin, and dsDNA breaks.

Conclusions:

• HPV genomes associate with host cellular transcriptional epicenters to maintain active viral gene expression during persistent infection.
• The susceptibility of these active chromatin regions to dsDNA breaks likely explains the propensity for viral DNA integration in HPV-associated cancers.