Lactate regulates cell differentiation of erythroid progenitor cells via histone lactylation modification

Lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-deoxy-<i>d</i>-glucose (2-DG) or exogenous lactate Na-La to decrease or increase intracellular lactate levels. The results showed the inhibition of glycolysis promoted erythroid progenitors' differentiation, blocked cell cycle, and reduced colony formation of colony-forming unit-erythroid (CFU-E), whereas elevated lactate levels delayed erythroid progenitors' differentiation and promoted CFU-E colony formation. We also found lactate levels directly regulated H3K14la intensity. Furthermore, we showed changes in H3K14la abundance and gene expression of the cell cycle and division-related genes <i>CCNB1</i>, <i>CFL1</i>, <i>CENPA</i>, and <i>GNAI2</i>, which were associated with stem cell pluripotency and differentiation. In conclusion, our study reveals lactate affects cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.