Researchers at the Institute of Functional Epigenetics (IFE), in collaboration with the Institute of Epigenetics and Stem Cells (IES), have discovered new mechanisms by which metabolism impacts our genes through epigenetic regulation. Their work focused on specific chemical changes in proteins to so-called histones, which package DNA into chromatin. They show that metabolism influences these chemical modifications on a specific histone, histone H4, and this in turn determines how DNA is read by the cell.
Metabolite-driven histone modifications change cell function. The so-called acylations are a specific type of chemical modification in histones. The authors demonstrated that multiple types of histone H4 acylations at lysine 16 (H4K16) act together to regulate gene expression. This work advances our understanding of the metabolic impact on our epigenome and lays the foundation for future investigations into how chromatin-based regulatory mechanisms contribute to health and disease.
“In our study, we systematically compared the effects of three histone modifications that result from the availability of metabolites—namely acetylation, propionylation, and butyrylation. Using biochemical approaches to reconstitute chromatin, biophysical assays, and computational modeling, we showed that all three modifications promote a more open chromatin structure and stimulate gene transcription. While H4K16 acetylation exerted the strongest effects, propionylation and butyrylation produced more moderate changes. Thus, the availability of specific metabolites may influence chromatin in slightly different ways,” explains Sandra Nitsch, postdoctoral researcher at the IFE and first author of the study.
“Our findings are relevant for disease, as we observed that mouse livers modeling metabolic disorders such as propionic acidemia and short-chain acyl-CoA dehydrogenase deficiency (SCADD) show altered histone H4 acylations,” adds Robert Schneider, Director of the IFE. “Surprisingly, we found that H4K16 acetylation, propionylation, and butyrylation changed across the entire genome. This means that these three acylations act in a concerted manner and can potentially affect all our genes! We are very excited about these findings, as we now believe that different histone acylations together provide resilience to metabolic challenges in disease settings.”
Original Publication
Nitsch et al., 2026: H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations. Molecular Cell.