Disruption of CTCF-YY1-dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription.

• Main Authors: Ieisha Pentland, Karen Campos-León, Marius Cotic, Kelli-Jo Davies, C David Wood, Ian J Groves, Megan Burley, Nicholas Coleman, Joanne D Stockton, Boris Noyvert, Andrew D Beggs, Michelle J West, Sally Roberts, Joanna L Parish
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2018-10-01
• Series: PLoS Biology
• Online Access: https://doi.org/10.1371/journal.pbio.2005752

The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to support virus replication. We report that the chromatin-organising CCCTC-binding factor (CTCF) promotes the formation of a chromatin loop in the HPV genome that epigenetically represses viral enhancer activity controlling E6/E7 expression. CTCF-dependent looping is dependent on the expression of the CTCF-associated Yin Yang 1 (YY1) transcription factor and polycomb repressor complex (PRC) recruitment, resulting in trimethylation of histone H3 at lysine 27. We show that viral oncogene up-regulation during cellular differentiation results from YY1 down-regulation, disruption of viral genome looping, and a loss of epigenetic repression of viral enhancer activity. Our data therefore reveal a key role for CTCF-YY1-dependent looping in the HPV life cycle and identify a regulatory mechanism that could be disrupted in HPV carcinogenesis.