Epigenetic regulation of cardiac tissue development by lysine lactylation

Heart disease stands as the foremost global cause of mortality. In rodents, the heart possesses the remarkable ability for cardiac regeneration within the first 7 days post-birth. Furthermore, the transition to an oxygen-rich environment and altered nutrient availability trigger a profound shift in cardiac energy metabolism immediately after birth. Lactylation, which translates metabolic adjustments into enduring gene expression patterns, has been recognized for its role in this process. However, its role in heart development has remained unexplored. In this study, we conduct an integrated study combining global proteomics, lactylome, and genome-wide RNA sequencing to elucidate the role of lactylation throughout postnatal heart development. Our findings demonstrate a remarkable increase in non-histone lactylation levels as early as 1 week (1 w) to 6 weeks (6 w) postpartum and remained elevated from 6 months (6 m) onwards. However, the histone lactylation showed the opposite trend. Additionally, we propose that histone 4 lysine 12 lactylation (H4K12la) acts as a pivotal upstream regulatory element in the early postnatal mouse heart, from 1 w to 6 w postpartum. Our findings strongly suggest a significant connection between lactylation and postnatal cardiac development and highlight its involvement in gene expression regulation, thus offering potential mechanisms for targeting heart diseases.