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Cornelia Vesely/Riem Gawish

Adjusting the base: (Epi)transcriptomic RNA modification in inflammation & host-microbiome crosstalk

Research Focus
Over 100 different RNA modifications are known and their influence on genetic information has sparked epitranscriptomic research impacting both biology and medicine. Adenosine to inosine deamination (A to I editing) by the RNA deaminases ADAR1 or ADAR2 is highly abundant and, as Inosine (I) is mostly read as guanosine (G), can recode messenger RNA (mRNA) and thereby protein sequences. Importantly, A to I editing is essential for life. Deletions of ADAR1 or ADAR2 are lethal in mice and mutations in ADAR1 in humans leads to interferon (IFN) responses and severe immune pathologyies. However, the precise role of particular RNA modifications in health and disease remains to be elucidated.

Main Objectives
RNA editing is an integral part of vital regulatory networks including self vs. non-self discrimination and host-microbiome crosstalk. We thus hypothesize that in the gut, RNA-editing is a key determinant in dysbiosis, inflammation and cancer. To tackle this, we combine “omic” approaches (metagenomics and transcriptomics), state-of-the-art mouse models of inflammatory bowel disease (IBD), microbial ecology cultivation-dependent and -independent techniques and a novel tissue-specific editing approach by CRISPR/Cas9. We aim to investigate in detail: 1) how editing impacts IBD; 2) the impact of fecal microRNAs and miRNA editing on the host-microbiota crosstalk; 3) the role of helicases in discriminating self vs. non-self RNA. Results will advance the field of epitranscriptomic research, improve the understanding of autoinflammation and potentially serve as a basis for the development of novel therapeutic tools against IBD and colon cancer.

Content of research
Imbalanced immune homeostasis of the gut, influenced by microbiota dysbiosis and genetic predisposition is at the basis of IBD. We are studying the consequences of RNA-editing in the context of inflammatory diseases of the colon using transgenic mice, cell biology methods, and transcriptomic approaches. As inflammatory bowel diseases (IBDs) are complex, multifactorial disorders we are employing an interdisciplinary approach including high throughput sequencing technologies, immunology, microbiome analysis and recently developed CRISPR/Cas9 tools.