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Start of funding 01.07.2011

Epigenetic effects of metabolic variation

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Histone modifying enzymes have a strong impact on gene expression and the pattern of histone modifications often reflects the activity state of a particular genomic region. Many histone-modifying enzymes use key metabolites such as SAM, NADH, Acetyl-CoA or 2-oxoglutarate as cofactors, which make them responsive to changes in metabolic states of a given cell. With the advent of large-scale proteomic and metabolomic studies, we can now start exploring causal relationship between metabolism and gene expression.

The expertise of the two groups involved in this application (Imhof, LMU and Sassone-Corsi, UCI) complements each other ideally to begin to study such a relationship in detail. The strength of these studies is particularly evident within physiological settings, which are currently investigated by this lab such as the molecular control of circadian rhythms.

Final report:
In the BaCaTeC project 3/2011-1 we investigated the relationship between metabolic states and gene expression (Katada et al., 2012). Initially we focussed on circadian changes of histone modification patterns and upon knockout of the AcCoA synthetase (Sahar and Vollmer manuscript in preparation) or of various Sirtuin enzymes (Masri and Barth, manuscript in preparation) . Initial results show that the concentration of AcCoA has variable impacts on distinct lysine residues suggesting a complex interdependency of metabolism and histone modifications. During the course of the project we realized that different metabolic states not only have a strong influence on histone modification patterns but also on the posttranslational modifications of other proteins. To explore reversible lysine acetylation dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock-/-) mouse liver by quantitative mass spectrometry (Masri et al., 2013). Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock-/- mice prompted us to link the acetylome to the circadian metabolome previously characterized in the Sassone-Corsi lab. Changes in enzyme acetylation over the circadian cycle were correlated with metabolite levels revealing biological implications connecting the circadian clock to cellular metabolic state.

Publications

• Katada S, Imhof A, Sassone-Corsi P. Connecting threads: epigenetics and metabolism. Cell. 2012 Jan 20;148(1-2):24-8.
• Circadian acetylome reveals regulation of mitochondrial metabolic pathways. Masri S, Patel VR, Eckel-Mahan KL, Peleg S, Forne I, Ladurner AG, Baldi P, Imhof A, Sassone-Corsi P. Proc Natl Acad Sci U S A. 2013 Jan 22. [Epub ahead of print]