Pathogen-infections lead to immediate upregulation of host-defence-genes, also called interferon-stimulated-genes (ISG). Many pathogens, including influenza-A-virus (IAV) counteract host ISG-expression. IAV-infection de-regulates transcription-termination so that non-terminated messenger (m)RNA are not translated and remain stuck in the nucleus as long-intergenic-non-coding (linc)RNA. The fate or function of these lincRNA remains largely unknown.
At non-induced ISG-promoters, transcription is constantly initiated, but prematurely terminated. ISG-induction then promotes transcript-elongation over termination. The decision to terminate or elongate is also controlled by epigenetic histone-modifications regulating protein-factor-binding to transcribed regions. Surprisingly, premature-termination-factors are also involved in lincRNA transcription-termination and termination-defects observed upon IAV-infection may be related to extended inhibition of premature-termination.
You will work at the exciting interphase of basic transcriptional regulation and host-pathogen-interactions and ask:
1. How are influenza-lincRNA made? You will test the hypothesis that influenza-induced lincRNA are generated through the same pathways as premature-transcription-termination. You will use several transcriptomic techniques to map epigenetic changes and chromatin-association or composition of termination-complexes.
2. Are influenza-lincRNA good or bad for the cell? RNA, if left too long in the nucleus is known to induce DNA damage. You will probe influenza-lincRNA- stability and test if they induce DNA-damage feeding back to apoptosis. Alternatively, influenza-lincRNA may help maintain nuclear chromosomal-structure-organisation.
3. How does IAV-infection change gene expression? You will establish a genetic screen to identify novel factors involved in influenza-lincRNA generation.
In summary, using system-biological approaches you will elucidate how different transcription-termination-pathways control gene expression during host-pathogen-interactions. Due to conservation, your insights are likely transferable to cancer-biology and development.