Deciphering the role of histone acetyltransferase CHM in starvation survival under changing temperature conditions

• Applicant: Dr. Shahaf Peleg
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458246576

In an ever-changing environment, adaptation is critical to an organism’s survival. One environmental challenge organisms can face is food scarcity. Identifying the molecular mechanisms that facilitate survival under starvation could provide insightful knowledge to promote better usage of dietary resources in various animals.One molecular mechanism allowing organisms to adapt to stressful events is epigenetic regulation, which modulates gene transcription. One epigenetic modification, histone acetylation, alters chromatin accessibility to enable transcription of downstream target genes involved in various biological pathways. For example, histone acetylation is implicated in key metabolic processes by which organisms cope with starvation. However how histone acetylation levels are linked to survivorship during starvation remains less understood. Our previous work in a Drosophila mutant for the lysine acetyl transferase CHM (chm) identified the histone 4 lysine 12 acetylation (H4K12ac) motif as a major target of CHM. Chm mutants display lower H4K12ac levels in midlife, extended lifespans, and better midlife motor activity. Interestingly, our preliminary data suggest that chm mutant flies maintained at the reduced temperature of 23°C exhibit reduced survivorship upon starvation, compared to flies maintained at the normal temperature condition of 25°C. Further, flies maintained at 23°C showed reduced H4K12ac (measured by mass spectrometry) and impaired gene expression (determined by RNAseq) during starvation. Notably, expression of Gnmt, a methyltransferase involved in the response to starvation, was reduced in chm mutants under starvation at 23°C. Histone acetylation reactions highly depend on acetyl-CoA availability derived from metabolic activity. As the rate of acetyl-CoA metabolism is believed to decrease in colder temperature, we hypothesized that lower acetyl-CoA levels at 23°C may be responsible for reduced H4K12ac in chm mutants, and therefore for the down regulation of various genes, including Gnmt.In this project we propose to define both the upstream and downstream mechanisms that underlie the temperature-sensitive survivorship of chm mutants under starvation. First, we will determine whether reduced acetyl-CoA metabolism in flies maintained at 23°C mechanistically explains the reduced histone acetylation levels in starved chm mutants at 23°C vs 25°C. Second, we will identify the genes differentially regulated in chm mutants during starvation at 23°C and characterize H4K12ac at these genes, as well as at the Gnmt gene. In addition, we will investigate the possible causal link between GNMT levels and the response to starvation. Our results will provide important insights into the regulation of the starvation response by a metabolism-epigenetics connectivity. Furthermore, this work may inform novel approaches for improving energy utilization by animals and therefore have practical benefits in times of shifting climate change.

• DFG Programme: Research Grants