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Yin Yang 1 is a potent activator of human T lymphotropic virus type 1 LTR-driven gene expression via RNA binding

Significance Human T lymphotropic virus type 1 (HTLV-1) is a retrovirus that mainly transforms CD4+ T cells, ultimately leading to the development of adult T cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis, both of which have limited treatment options. A deeper understanding of how the virus hijacks host factors for replication is critical for the development of new therapies. In this study, we discovered that a host transcription factor, Yin Yang 1 (YY1) is a potent activator of HTLV-1 gene expression. Surprisingly, it does so by binding to viral RNA, instead of the classical DNA–transcription factor interaction. Our results provide insights into host–viral interactions, as well as the biology of cellular transcription factors. Yin Yang 1 (YY1) is a DNA-binding transcription factor that either activates or represses gene expression. YY1 has previously been implicated in the transcriptional silencing of many retroviruses by binding to DNA sequences in the U3 region of the viral long terminal repeat (LTR). We here show that YY1 overexpression leads to profound activation, rather than repression, of human T lymphotropic virus type 1 (HTLV-1) expression, while YY1 down-regulation reduces HTLV-1 expression. The YY1 responsive element mapped not to YY1 DNA-binding sites in the HTLV-1 LTR but to the R region. The HTLV-1 R sequence alone is sufficient to provide YY1 responsiveness to a nonresponsive promoter, but only in the sense orientation and only when included as part of the mRNA. YY1 binds to the R region of HTLV-1 RNA in vitro and in vivo, leading to increased transcription initiation and elongation. The findings indicate that YY1 is a potent transactivator of HTLV-1 gene expression acting via binding viral RNA, rather than DNA.