H3K18 lactylation marks tissue-specific active enhancers

Abstract

Background Histone lactylation has been recently described as a novel histone post-translational 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 island-containing 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.

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

“…As revealed by the presence of the postprandial lactate shuttle ( 4 ), lactate is the metabolic intermediate involved in dietary carbohydrate distribution and disposal. Mechanisms by which lactate operates to control energy substrate partitioning include mass action ( 3 ), allosteric binding ( 23 , 24 , 248 ), ROS production ( 32 ), canonical intracellular signaling ( 249 ), central nervous system signaling via substrate supply ( 153 ) and protein lactylation ( 148 ), and gene expression via histone lactylation ( 30 , 250 ). With all due respect to classical and contemporary discoveries in metabolic regulation, it is reasonable to assert that “lactate is the major myokine and exerkine” because of its abundance, dynamic range of concentration change, effect on cell redox and multiple independent and coordinated regulatory effects on major metabolic pathways in diverse tissues ( 115 , 251 ).…”

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“…It was first reported that there were 28 lactate sites in histones, which were reported by Zhao et al Later, Meyenn et al found that global H3K18 lactylation distribution marked the active promoter regions of some highly expressed genes, which was positively correlated with gene expression. 3,172 In recent years, the study of epigenetic modifications has gained significant attention, and histone lactylation has been discovered to play a crucial role in immune regulation, inflammation, cancer, and other diseases. [173][174][175][176] The p300 of HAT family mediates the lactylation modification of H3 and H4, while the deacetylases HDAC1-3 and SIRT1-3 have the de-L-lactylase enzyme activity.…”

The chromatin signatures of enhancers and their dynamic regulation

“…Hence, while a mark tightly correlated with enhancer activity, H3K27ac may not be essential for enhancer function. Other histone marks were also found on putative enhancers but their roles requires to be clarified [ 48 , 142–144 ]. For example, the methylation of the lysine 79 of the histone H3 (H3K79me) was identified on a subset of active enhancers, but its roles in maintenance and regulation of active enhancer stage has not been addressed [ 50 , 143 , 145 ].…”