Like the energy drink cans and protein bar wrappers that litter the table after an epic writing session, by-products generally represent undesirable items created during the generation of a more desirable object. Recycling can put some writing by-products to further use, and studies have now highlighted that biological by-products derived from cellular metabolism can also be put to use by our cells, by modifying histones.
In related studies of cancer cell metabolism, the Warburg effect refers to the phenomenon by which cells favor glycolysis with the production of lactate as a by-product; however, while the Warburg effect has been linked to multiple cellular processes and several disease states, we lack an understanding of how this metabolic pathway influences physiology and disease. Intrigued by this metabolic puzzle, a never wasteful team from the labs of Lev Becker and Yingming Zhao (University of Chicago, Illinois, USA) upcycled some ideas from related studies and asked if and how the metabolic by-product lactate regulates gene expression.
Let’s discover how Zhang and colleagues helped to decipher the Warburg effect via their analyses of various mouse and human cells:
- Proteomic analysis of human cancer cell histones uncovered histone lactylation as an in vivo post-translational modification
- A mass shift indicated the addition of a lactyl group to a lysine residue, and the authors validate histone lactylation through a range of orthogonal techniques
- Overall, analyses uncover 28 lactylation sites on core histones
- Alterations to metabolism and lactate production regulate histone lactylation
- Proteomic analysis shows increased histone lactylation following isotopic glucose treatment
- Quantitative proteomics analyses reveal that stimulated histone acetylation peaks after six hours, but lysine lactylation peaks only at 24 hours, following glucose treatment
- Enhanced mitochondrial metabolism reduces lactate production and histone lactylation, while enhanced glycolysis increases lactate production and histone lactylation
- Two model systems strengthen the claim that metabolism alters histone lactylation
- Hypoxia and the polarization of macrophages to an M1 phenotype both reprogram cell metabolism towards glycolysis, thereby increasing lactate production and histone lactylation
- Surprisingly, increases in H3K18la levels at promoter sequences during the late stages of M1 macrophage polarization drive the expression of associated M2-like (pro-regenerative) genes
- Importantly, the team prove that histone lactylation directly stimulates gene transcription
- RNA-seq and ChIP–seq demonstrated H3K18la enrichment at promoter regions for genes with steady-state mRNA expression
- Cell-free, recombinant chromatin templated histone modification and transcription assays confirm that histone lactylation induces gene transcription while providing evidence that p300 may represent a lactylation “writer”
Co-senior author Lev Becker shares, “That a single metabolite can have such a powerful effect on immune cell function is both remarkable and surprising. Our discovery of histone lactylation and its impact on macrophage biology serves as a blueprint to understand how lactate alters other cell types and unravel the mysteries of the Warburg effect and its impact on human disease.”
While the team provides evidence for a novel epigenetic mechanism behind the Warburg effect, they also suggest that that histone lactylation may represent a common and widespread modification and may act as an endogenous ‘lactate clock’ to alter macrophage polarization towards the pro-regenerative phenotype to aid the resolution of tissue inflammation or damage.