Physiological role of m6A epitranscriptomic modifications in intestinal inflammation

• Applicant: Professorin Dr. Sabrina Jabs
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504665010

The intestinal microbiota has an immense impact on host physiology and interacts with host metabolism in many different ways, e.g. for the supply of nutrients, the modulation of the immune system and defense mechanisms against pathogens. An imbalanced microbiota is associated with the development of metabolic syndrome, cancer or inflammatory diseases. Although it is known that microbial regulation of host gene expression can be mediated by bacterial metabolites, many aspects of bacteria-host interactions and their involvement in developing disease are still incompletely understood. We could recently show that the microbiota influences the posttranscriptional mRNA modification m6A in mouse tissues. Specifically, transcripts related to inflammation, antibacterial responses and metabolic processes were methylated in dependence of the microbiota, among them several known susceptibility genes for inflammatory bowel disease. Mechanistically, these so-called epitranscriptome modifications regulate gene expression by modulation of transcript splicing, stability and translation. In addition to their critical role in embryonic stem cell differentiation or cancer, absence of the m6A writer proteins Mettl3/Mettl14 has been shown to contribute to the development of colitis in mice, suggesting an important role of this modification in inflammatory diseases. Since these diseases are multifactorial, one of the factors being the microbiota, we hypothesize that the expression of risk genes for inflammatory diseases is regulated by the microbiota via m6A posttranscriptional modifications. We plan to analyze inflammatory disease-related transcripts that are differentially methylated between conventional and germ-free mice which we identified previously. We will determine the stability and expression of their m6A-deficient transcript mutants and their involvement in pro-inflammatory signaling in vitro in cultured cells and organoids and in vivo by generating knock-in mice. Since our previous data suggests a microbiota-dependent expression of the alternative m6A writer protein Mettl16, we will additionally generate conditional Mettl16 KO mice in CD4+-T-cells and in epithelial cells to define its role in colitis and to identify Mettl16 targets upon inflammation. Focusing on regulators of the epitranscriptome, but more importantly the physiological role and mechanistic function of distinct modifications in disease-related transcripts we aim to unravel disease mechanisms that might help to develop new strategies for the treatment of chronic inflammation and potentially other microbiota-related diseases.

• DFG Programme: Research Grants