PIF2024 - A DIRECT METABOLIC ROLE FOR HISTONE METHYLATION (PID2023-151711OA-I00)

Epigenetic marks are commonly thought of as a clean, almost digital means of encoding information to instruct transcription. However, as biochemical processes they are intrinsically embedded in the wider metabolism of the cell. Not only can this affect epigenetics, but by the massive cellular abundance of e.g. histones, epigenetic processes can be seen as metabolic processes in their own right, with a wider direct impact on metabolic networks. Genetic alterations of histone methyltransferase (HMTs) genes are frequently associated with cancer, which researchers typically assume is related to transcriptional dysregulation. However our previous work, which found evidence for a direct metabolic role for histone methylation in humans, suggests that sometimes the oncogenic roles of HMTs may be metabolic in nature. The aim of this project is to investigate the integration of histone methylation into metabolic networks. Firstly, we will use the powerful genetic tools of the model organism C. elegans to screen for metabolic co-regulators of HMT genes, which would establish the regulation of HMTs as a metabolic process and identify potential drug targets for modulating HMT expression. Secondly, we will test a novel hypothesis proposing a direct metabolic role for histone lysine tri-methylation in C. elegans supporting mitochondrial fatty acid oxidation by boosting the production of carnitine, which is synthesised from the precursor trimethyllysine.