Project ID CM-HD2023_29

ThemeCM-HD

Co Supervisor 1A Infectious Diseases/SIMS/FOLSMWebsite

Co Supervisor 1B Medical & Molecular Genetics/School of Basic and Medical Biosciences/FOLSMWebsite

Immune-Control of Gene Expression During Host-Pathogen Interactions

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.

One representative publication from each co-supervisor:

• Mischo HE, Chun Y, Harlen KM, Smalec BM, Dhir S, Churchman LS, Buratowski S. Cell-Cycle Modulation of Transcription Termination Factor Sen1. Mol Cell. (2018);70(2):312-326.e7. doi: 10.1016/j.molcel.2018.03.010.

• Amante, S.M., Montibus, B., Cowley, M., Barkas, N., Setiadi, J., Saadeh, H., Giemza, J. Contreras Costillo, S., Fleischanderl, K. Schulz, R. and Oakey, R.J. Transcription of intragenic CpG islands influences spatiotemporal host gene pre-mRNA processing. Nucleic Acids Research. 2020 Sep 4; 48 (15) 8349-8359. doi: 10.1093/nar/gkaa556. PMID 32621610.