Histone lactylation-mediated chromatin dynamics facilitate maintenance of hematopoietic stem and progenitor cells and regulation of erythropoiesis

Hematopoietic stem and progenitor cells (HSPC) rely more on glycolysis than lineage-restricted progenitors, generating high levels of lactate that may influence chromatin regulation. Here, we investigate dynamic histone lactylation and its regulatory roles in HSPC maintenance and early erythropoiesis. We find that HSPCs exhibit higher glycolytic activity, lactate levels, and histone lactylation compared with erythroid progenitors (Ery-Pro). Integrated CUT&Tag, ATAC-seq, and RNA-seq analyses reveal that histone lactylation is positively associated with gene expression and chromatin accessibility. Functional studies ex vivo and in vivo show that elevated histone lactylation delays erythroid differentiation, prolongs the progenitor state, enhances erythroid expansion, and promotes HSC maintenance and post-transplantation reconstitution. Mechanistically, histone lactylation contributes to the upregulation of the transcription factor FLI1, a positive regulator of HSPC maintenance, and genes encoding negative regulators of the cell cycle, thereby slowing cell-cycle progression to preserve HSPCs. Notably, although histone lactylation and acetylation at the same lysine residues show similar chromatin occupancy patterns, lactylation correlates more strongly with chromatin accessibility. Together, these findings support a role for histone lactylation in HSPC maintenance and early erythropoiesis, with potential implications for HSC culture optimization and therapeutic development. Histone lactylation promotes hematopoietic stem and progenitor cell maintenance, delays erythroid differentiation, and enhances erythroid expansion by modulating chromatin accessibility and regulating the expression of FLI1 and cell-cycle genes.