Figure 3.

Model showing the role of YY1 during HPV life cycle in undifferentiated (A) and differentiated keratinocytes (B). The life cycle of HPVs is strongly associated with the differentiation program of the epithelial cells. HPV infection initiates in the undifferentiated basal epithelial cells where the expression of E6 and E7 genes is restricted by the establishment of a CTCF (CCCTC-binding factor)–YY1-dependent chromatin loop of epigenetically repressed chromatin (A). Upon epithelial differentiation, the production of early transcripts of virus is increased. In differentiated keratinocytes, the elevated E6 and E7 protein levels are important to maintain host cell proliferation and provide viral access to the host cell DNA replication machinery. This is synchronized with a differentiation-induced reduction in YY1 levels, which releases the repressive chromatin loop and attenuates the recruitment of polycomb repressor complexes (PRC1 and PRC2) and inhibits H3K27me3 (trimethylation of histone H3 at lysine 27) deposition. Increased accessibility and reduced H3K27Me3 at the viral enhancer sites result in derepression of the early promoter, increased RNA Pol II recruitment, and H3K4me3 (trimethylation of histone H3 at lysine 4) deposition, resulting in increased E6/E7 oncogene expression.