Disruption of methionine metabolism drives erythroid cell fate reprogramming by remodeling the H3K4me3 landscape.

The methionine cycle plays critical roles in cell fate determination by shaping epigenetic landscape, yet its function in human erythropoiesis remains undefined. Here, we show that disruption of methionine metabolism by compromising the key enzyme adenosylhomocysteinase (AHCY) reshapes H3K4me3 landscape, causing erythroid cell fate reprogramming. AHCY deficiency severely impaired erythroid differentiation and expansion, leading to the generation of nonerythroid lineage hematopoietic cells, including stem/progenitor cells and immune cells, as evidenced by single-cell RNA-seq, and pseudo temporal analysis delineated a precise dedifferentiation trajectory, revealing erythroblasts transitioning back to MEPs and HSCs. Moreover, the human hematopoietic system could be reconstituted in the immunodeficient NCG-X mice by transplanting AHCY-deficient erythroblasts. Mechanistically, AHCY deficiency reduced global H3K4me3 levels and altered its genomic distribution, resulting in the upregulated expression of nonerythroid transcription factors and downregulated expression of erythrocyte lineage-specific transcription factors. Integrated single-cell analyses identified transitional states with diminished AHCY in the erythroblasts of a patient with acute myeloid leukemia (AML). Further flow cytometry confirmed the reduced H3K4me3 level in patient-derived erythroid cells. Erythroblasts isolated from patients with AML with reduced H3K4me3 exhibited a dedifferentiation potential into progenitor-like states. Our findings reveal a metabolic-epigenetic axis governing cell fate reprogramming in human erythropoiesis and provide insights into leukemia-associated anemia.