Histone modifying enzymes as direct regulators of metabolic reprogramming: Towards a New Paradigm

Project Information

MetabolACE

Grant agreement ID: 890750

DOI

10.3030/890750

Project closed

EC signature date 7 April 2020

Start date 1 January 2021

End date 31 December 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 145 941,12

EU contribution

€ 145 941,12

Coordinated by

UNIVERSITY OF CYPRUS
Cyprus

Periodic Reporting for period 1 - MetabolACE (Histone modifying enzymes as direct regulators of metabolic reprogramming: Towards a New Paradigm)

Reporting period: 2021-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Our hypothesis is that these enzymes consume large amounts of key metabolites and thus drive metabolic rewiring by altering their abundance. Using a combination of epigenetics and metabolomics techniques, researchers will investigate how histone acetyltransferase (HAT) activity affects the pool of acetyl coenzyme A (Acetyl-CoA) in cells. The work will establish a new fundamental link between epigenetics and metabolism in both health and disease. Should our results show that HATs modify histones via metabolic rewiring, this will be a major breakthrough in the field of biological sciences as a new concept for epigenetic regulation will be developed, which will be the commencing point for important future work in diabetes, epigenetics, metabolism and more.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Using a toolkit that integrates epiproteomics and metabolomics with stable isotope tracer studies, we show that depletion of HATs in murine hepatocytes leads to accumulation of lipids as well as lipid droplets. This increase in lipids in HAT-depleted cells resulted from carbon atoms flowing from the deacetylation of doubly labeled acetylated histone marks to fatty acids, making histone-derived acetyl-CoA an important source for lipid synthesis. In fact, we demonstrate that the synthesis of HDAC-derived acetyl-CoA mediated from ACSS2 is essential for lipid droplet formation. We also demonstrate that ACSS2-mediated increase in lipid content in HAT-depleted cells is not HAT-specific but due to their common feature of consuming acetyl-CoA. Overall, our findings demonstrate a novel path through which histone-modifying enzymes can directly contribute to lipogenic acetyl-CoA pools, contributing to metabolic disorders such as fatty liver. Our proposed model provides a novel mechanistic role of HATs, HDACs and ACSS2 in the metabolism-epigenetics nexus, where histones can act as metabolic reservoirs and the relative activity between HATs and HDACs acting on these reservoirs can determine lipogenic acetyl-CoA pools. This emerging concept has been proposed by recent reviews and might have important implications in diseases with increased rates of lipid synthesis, such as non-alcoholic fatty liver disease.

The results of the project were disseminated to the following conferences:
1. 18th Annual Conference of the Metabolomics Society
Valencia, Spain 2022
June 19-21
Poster presentation title: “Acetyltransferases as direct regulators of metabolic reprogramming: Towards a New Paradigm”
2. 10th International Multithematic Bio-Medical Congress (IMBMC) Scientific Cyprus
Nicosia, Cyprus 2022
November 3-5
Oral Presentation title: “Histone modifying enzymes as direct regulators of metabolic reprogramming in fatty liver”
3. 17th Annual Conference of the Metabolomics Society, Online
2021
Oral Presentation title: Histone acetyltransferase NAA40 affects insulin signalling by modulating acetyl-CoA levels and lipid synthesis
4. EMBO | EMBL Symposium: Metabolism Meets Epigenetics Online
Wed 11/17/2021 - Sat 11/20/2021
Poster presentation title: Histone acetyltransferase NAA40 affects insulin signalling by modulating acetyl-CoA levels and lipid synthesis

In addition to conferences, the fellow presented the MetabolACE project to a departmental seminar, sharing results with the Biological Sciences Department of UCY.

The results of the project as anticipated resulted into two publications:

1. Charidemou, E., Tsiarli, M.A. Theophanous, A. et al. Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis. BMC Biol 20, 22 (2022). https://doi.org/10.1186/s12915-021-01225-8
2. Charidemou, E. et al.(In preparation)

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The main objective of the project is to characterise whether altering the activity of HATs by environmental or genetic perturbations would consequently change the consumption of acetyl-CoA by histones and thereby alter the intracellular levels of this metabolite inducing metabolic rewiring and subsequently influencing insulin sensitivity [since the expression levels of these HATs are dysregulated in obesity-related insulin resistance]. Due to the fact that is challenging to uncouple the transcriptional effects of HATs on metabolism from their direct consumption of metabolites, we used three different acetyl-CoA consumption-capacity HATs to determine whether our hypothesis is a general mechanism for HATs (and not a HAT-specific or PTM-specific effect) to control metabolism and whether the consumption level will have different impacts on the phenotype in vitro. Specifically, we performed a an integrative state of the art experiment combining stable isotope tracing for metabolomics and epipoteomics. The relative flux of 13C-label between histones marks, acetyl-CoA levels and lipids determined the comparative consumption of acetyl-CoA by these HATs. Overall, the activities of this objective defined the spatial metabolic rewiring of HAT-deficient hepatocytes.

project summary