A genome-wide analysis of YY1 and TFAP2 competition on overlapping motifs reveals their roles in HPV-induced carcinogenesis

The long non-coding RNA lnc-FANCI-2 acts as a host defense RNA and is highly expressed in HPV-positive cervical lesions. Its activation relies on the binding of the transcription factor YY1 to two conserved motifs in its promoter. We used DNA oligo pull-down combined with mass spectrometry to identify proteins binding to the lnc-FANCI-2 promoter, discovering new TFAP2 family members that compete with YY1 for binding at overlapping sites. In primary epithelial cells, TFAP2 binding led to lnc-FANCI-2 silencing. However, in HPV-positive cancer cells, increased YY1 levels displaced TFAP2, alleviating repression. Genome-wide predictions using the JASPAR database identified thousands of YY1 and TFAP2 competition binding sites (CBSs), many overlapping with CHIP-seq peaks for YY1, TFAP2A, and TFAP2C, predominantly in promoter regions. We validated competition at two CBSs in the promoter and found it likely regulates cancer-related genes PPP1R15B and LRRC37A. This suggests that YY1 and TFAP2 competition might influence a broader transcriptional regulation network in HPV-induced cancer. This study reveals a novel transcriptional antagonism mechanism affecting lnc-FANCI-2 and other cancer-related genes, highlighting YY1 and TFAP2 as potential therapeutic targets in HPV-driven carcinogenesis.