H3K18 lactylation marks tissue‑specific active enhancers

Background: Histone lactylation has been recently described as a novel histone posttranslational modification linking cellular metabolism to epigenetic regulation. Results: Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG islandcontaining promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. Conclusions: Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers.ETH Zurich ETH Zurich core fundingEuropean Research Council (ERC) European Commission 803491Botnar Research Centre for Child Health Multi-Investigator ProjectWorld Food System Center of ETH ZurichIntegrative Food and Nutrition Center of EPF