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

## TL;DR

Lactate influences the differentiation of blood cell precursors by modifying histone proteins, affecting gene activity.

## Contribution

This study reveals lactate's role in erythroid progenitor differentiation through histone lactylation.

## Key findings

- Inhibiting glycolysis promotes erythroid progenitor differentiation and reduces colony formation.
- Elevated lactate levels delay differentiation and increase colony formation.
- Lactate regulates H3K14la levels and expression of cell cycle-related genes.

## Abstract

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-d-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 CCNB1, CFL1, CENPA, and GNAI2, 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.

•Altered lactate levels regulate erythroid progenitor cell differentiation•Lactate levels directly regulated H3K14la abundance•2-DG treatment regulates the expression of cell cycle and division-related genes•Expression of cell cycle and division-related genes related to H3K14la abundance

Altered lactate levels regulate erythroid progenitor cell differentiation

Lactate levels directly regulated H3K14la abundance

2-DG treatment regulates the expression of cell cycle and division-related genes

Expression of cell cycle and division-related genes related to H3K14la abundance

Biochemistry; Molecular biology; Cell biology