Transcription Factors-RNA interaction: a new layer of cellular regulation
Gene expression is a complex process tightly regulated by various proteins, including DNA-binding proteins (DBPs) and RNA-binding proteins (RBPs). However, little is known about proteins that can bind both DNA and RNA, referred to as DNA-RNA binding proteins (DRBPs). In this study, we identified over 40 transcription factors (TFs) including the pluripotent factors OCT4 and STAT3, the latter known also for it’s roles in immune system and cancer progression. Using enhanced-CLIP we found that STAT3 directly interacts the long non-coding RNA involved in DNA stability, NORAD. Further, by conducting extensive functional analyses we show that the binding of NORAD to STAT3 has a key role in anti-viral response both in pluripotent and fully differentiated cells. In healthy cells, it effectively silences the antiviral pathway, while upon infection it allows a rapid shift towards activation of, viral defense genes. Intriguingly, we found that the function of NORAD is unique to humans and not observed in mice, despite the conservation of other functions across mammalian evolution.
The identification of a direct interaction between STAT3 and NORAD, its mechanism and its function, adds a new dimension of knowledge regarding DRBPs’ roles in rapid cellular response to the environment. Additionally, this human-specific function of NORAD underscores the contribution of this study to understanding species-specific gene regulation.