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

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 CTCFassociated 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. Author summaryOncogenic human papillomavirus (HPV) infection causes cancers of the anogenital and oropharyngeal tracts.HPV infects undifferentiated basal cells of the epithelium at these body sites and expresses low levels of viral early genes, required for replication of the viral genome.In normal epithelia, cellular migration away from the basal layer induces cell cycle exit and differentiation.However, in an HPV-infected cell, differentiation induces increased transcription of the viral early genes to prevent cell cycle exit, supporting amplification of the viral DNA.In this study, we show that the HPV genome recruits the cellular transcriptional regulators CTCF and YY1, which coordinate an epigenetically repressed