Understanding the function of ctcf recruitment to oncogenic human papillomavirus genomes during the viral life cycle

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Pentland, Ieisha (2018). Understanding the function of ctcf recruitment to oncogenic human papillomavirus genomes during the viral life cycle. University of Birmingham. Ph.D.

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Abstract

The CCCTC-binding factor (CTCF) is a DNA binding protein essential for genome-wide organization of chromatin. A conserved CTCF binding site was identified in the E2 open reading frame of high-risk HPV types, but was absent in low-risk HPV types. Abrogation of CTCF binding at the E2 site in HPV18 genome containing primary human foreskin keratinocytes causes significant upregulation of transcripts encoding the early viral oncoproteins E6 and E7, resulting in epithelial hyperproliferation. Notably, abrogation of CTCF binding results in a more open conformation within the viral long control region (LCR), which is positioned 3 kilobases upstream of the E2-CTCF binding site. In addition, there is a loss of recruitment of the transcriptional repressor protein YY1 and of the polycomb repressive complexes. Chromatin conformation capture was used to demonstrate DNA looping between the E2-CTCF binding site and the YY1-bound viral LCR. The formation of this chromatin loop is dynamic and reduced upon epithelial differentiation. Together, these data show that high-risk HPV genomes recruit CTCF to the E2 ORF to form a repressive chromatin loop with the YY1-bound LCR to control viral oncoprotein expression. Ultimately this strategy will allow the virus to coordinate life cycle events to maintain a persistent infection.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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