Human papillomavirus integration transforms chromatin to drive oncogenesis

Area of Science:

• Oncology
• Virology
• Genomics

Background:

• Human papillomavirus (HPV) is a primary driver of cervical and head and neck cancers.
• HPV integration into the host genome is common in tumorigenic strains and may alter gene expression, contributing to cancer.
• The role of chromatin state changes at integration sites in HPV-driven tumorigenesis is investigated.

Purpose of the Study:

• To investigate if HPV integration alters chromatin state and gene expression near integration sites.
• To determine if HPV integration introduces new transcription factor binding sites that invoke chromatin changes.
• To analyze the impact of HPV integration on gene essentiality in HPV-positive tumors.

Main Methods:

• Chromatin accessibility assays and ChIP-seq were used to analyze CTCF binding and chromatin state.
• Gene expression and alternative splicing changes near HPV integration sites were analyzed.
• Data from The Cancer Genome Atlas (TCGA) HPV-positive tumors were analyzed for gene essentiality.

Main Results:

• HPV integration correlates with altered chromatin state and gene expression near the integration site.
• A conserved CTCF binding site in the HPV genome binds CTCF and is associated with increased chromatin accessibility near integration sites.
• HPV integration upregulates genes with higher essentiality scores in HPV-positive tumors.

Conclusions:

• HPV integration can introduce CTCF binding sites, reorganizing chromatin and upregulating essential genes in some HPV-positive tumors.
• These findings highlight a novel role for HPV integration in cancer development.
• Understanding this mechanism may offer new therapeutic strategies for HPV-driven cancers.