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Selected Publication:
Zhang, F.
Regulation of Arginine Methylation in Health and Disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2021. pp. 174
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- Authors Med Uni Graz:
- Advisor:
- Madl Tobias
- Malli Roland
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- Abstract:
- Post translational arginine methylation (ArgMet) is important for many cellular processes and biological functions including metabolic homeostasis. The role of ArgMet in (patho)physiology still remains poor understood due to the lack of applicable detection methods. Here, we developed a simple, fast and robust protocol for absolute quantification of global protein arginine methylation based on Nuclear Magnetic Resonance (NMR) spectroscopy. This approach enables the detection of ArgMet, together with the analyses of metabolic profiles in an almost unlimited number of biological matrices, including, but not limited to, cells, biological fluids and tissues. In our study, arginine methylation represents a high prevalent post-translational modification. Besides, arginine methylation is coupled with the metabolic cycle and can be modulated by small molecules and metabolites. Arginine methylation regulation also involved into cancers, differentiation and ageing. Methionine restriction has been reported to extend lifespan and suppress tumor growth depending on flux in the one carbon metabolism. Given that ArgMet is strongly dependent on the essential amino acid methionine, which is a precursor to S-Adenosyl-L-methionine, we hypothesize that ArgMet is strongly coupled to metabolism. Metabolic reprogramming is a hallmark of cancer and ageing. We undertook an extensive combined proteomics and metabolomics analysis of serum, cancer tissues and peritumoral tissue from 200 hepatocellular carcinoma patients demonstrating sized-dependent metabolic reprogramming. We found dysregulated enzyme and metabolites related with glycolysis, the tricarboxylic acid cycle and pyrimidine synthesis with increased tumor size. Several metabolite biomarkers offered prognostic information for patients and they can be combined with clinical pathological data. We built and validated the integrated clinicopathological and metabolomic model to predict the 5-year recurrence. Given the high therapeutic potential, it will be interesting to combine metabolites and ArgMet inhibitors via reprogramming of one carbon metabolism. Altogether, our data emphasize that targeting cancer metabolism/ArgMet will open new avenues for effective therapies for hepatocellular carcinoma in future. We also integrated a metabolomic analyses of ageing tissues based on NMR spectroscopy. Greatly different metabolic profiles of tissues were regulated by ageing and several universal metabolic biomarkers of ageing were identified. The pathways perturbed in ageing demonstrate organ-specific and more-global effects of ageing and point to mechanisms that could potentially be counter-regulated pharmacologically to treat ageing and age-associated diseases. Besides, identified metabolite biomarkers can be evaluated for the effectiveness of ageing tissues or organs model and provide an assessable indicator for senolytic drug candidates. The significant decreased ArgMet might be due to reduction of methionine level in aged spleen. It will be interesting to search drugs to extend lifespan through combining metabolomic and ArgMet targets. In summary, our method provides new tools to study the important (patho)physiological role of protein arginine methylation.