OCT4 Negatively Regulates the Transcriptional Programming of the Human Adenovirus Early Region 3 Immune Evasion Genes

Genomes of viruses are constrained by the virions’ nanoscale, and viral nucleotide sequences without function are a luxury. Yet the double-stranded DNA genome of human adenovirus (HAdV) contains large regions without known purpose. Using TRANSFAC and ChIP-Seq analysis, we identified binding of OCT4 (octomer-binding transcription factor 4) to a noncoding region of HAdV-D37 DNA. Manipulation of OCT4 expression impacted viral E3 gene transcription and gp19k protein expression, altering subsequent MHC class 1 expression. These effects were specific to OCT4 binding to the adenovirus 5ʹ inverted terminal repeat (ITR) within nucleotides 101-159. Using targeted mutations to OCT4, we found one of two OCT4 binding motifs in the ITR to be crucial for repression of E3 gene expression. In OCT4-siRNA treated cells, E3 RID-α gene expression was also upregulated to inhibit pro-apoptotic signals, suggesting that OCT4 binding also indirectly represses viral replication. Consistent with a role for transcription factors in epigenetic modification during infections, OCT4 knockdown also reduced histone H3 acetylation and DNA methylation. In stem cells, OCT4 sustains pluripotency, whereas in somatic cells, OCT4 plays a dispensable role in self-renewal and maintenance. Herein, we show that OCT4 binding also confers a previously unidentified function to non-coding adenovirus DNA.