EZH2 and metabolic regulation
Heart failure (HF) is pathological condition corresponding to the partial inability of the heart to perform its role as a pump in order to complete the organism’s energy needs and provide enough oxygen and nutrients. This pathology is a major concern in terms of public health due to population aging and the diversity of cardiovascular risk factors, which prevalence increases with aging. Under physiological conditions, approximately 70% of cardiac energy is produced by mitochondrial oxidation of fatty acids1,2. Nowadays, it is well established that a transition of cardiac metabolism, from energy production by fatty acid oxidation to 4/22 anaerobic glycolysis, occurs during HF development. Until now, usual therapies aim to improve cardiac contractility but fail to restore an efficient energy metabolism. Thus, targeting energy metabolism, and in particular the use of energy substrates during metabolic transition process, has become a major area of research to identify alternative or complementary therapeutic approaches for the treatment of HF.
In this context, the epigenetic enzyme EZH2 has been shown to play a critical role in the transcriptional regulation of various enzymes expression involved in the previously described cardiac metabolic transition3. Moreover, studies performed at the UMR INSERM U1096, has highlighted an improvement in cardiac function after myocardial infarction (one of the main causes of heart failure), in vivo in mice, after treatment with a specific pharmacological inhibitor of EZH24. We hypothesized that EZH2 inhibition limits the metabolic transition from fatty acid metabolism toward anaerobic glycolysis and thus might prevent HF development.
References: 1. Doenst, T., T.D. Nguyen, and E.D. Abel, Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res, 2013. 113(6): p. 709-24. 2. Wende, A.R., et al., Metabolic Origins of Heart Failure. JACC Basic Transl Sci, 2017. 2(3): p. 297- 310. 3. Pepin, M.E., et al., Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure. Lab Invest, 2019. 99(3): p. 371-386. 4. Rondeaux, J., et al., Ezh2 as an epigenetic checkpoint regulator during monocyte differentiation: a potential target to improve cardiac repair after myocardial infarction. Under revision Nat Commun, 2021, bioRxiv preprint doi.org/10.1101/2021.02.17.428828.
Theoretical knowledge: the candidate should have strong knowledge in integrated physiology, especially cardiac function and metabolism as well as heart failure physiopathology. The candidate should ideally have basic notions in molecular biology and more particularly in epigenetic modifications such as post-translational histone modifications.
Practical skills: the candidate should be familiar molecular biology (RNA extraction, RTqPCR and RNAsequencing) technics and mass-spectrometry more particularly concerning lipid metabolism analysis. Skills in bio-informatics analysis, cellular metabolism technics and isolation of murine cardiomyocytes would be highly appreciated