Human Papillomavirus Genomes Associate with Active Host Chromatin during Persistent Viral Infection

Area of Science:

• Molecular Biology
• Virology
• Epigenetics

Background:

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

Purpose of the Study:

• To investigate the association of HPV31 genomes with host chromatin structures.
• To determine if HPV31 genome localization correlates with active transcriptional regions and sites of DNA damage.

Main Methods:

• Utilized chromosome conformation capture techniques, including HiC and 4C-seq, to map HPV31 genome interactions with host chromatin.
• Integrated data from ATAC-seq (open chromatin) and ChIP-seq (Brd4, H3K27ac super-enhancers) to define host chromatin states.
• Correlated viral genome association sites with publicly available datasets for double-strand DNA breaks (dsDNA breaks) and HPV integration sites in cervical cancers.

Main Results:

• HPV31 genomes preferentially associate with transcriptionally active 'A' compartments of host chromatin.
• Viral genome localization strongly correlated with open chromatin regions (ATAC-seq) and super-enhancers (Brd4, H3K27ac ChIP-seq).
• HPV31 association sites overlapped significantly with known HPV integration sites in cervical cancers and regions prone to dsDNA breaks.

Conclusions:

• HPV31 genomes associate with host cellular transcriptional centers to ensure active viral gene expression during infection.
• The preference for transcriptionally active, dsDNA break-prone chromatin regions may explain the high frequency of viral DNA integration observed in HPV-associated cancers.