Epigenetic Regulation of Erythropoiesis: From Developmental Programs to Therapeutic Targets.

Erythropoiesis, the process driving the differentiation of hematopoietic stem and progenitor cells to mature erythrocytes, unfolds through tightly orchestrated developmental stages, each defined by profound epigenetic remodeling. From the initial commitment of hematopoietic progenitors to the terminal enucleation of erythrocytes, dynamic changes in chromatin accessibility, transcription factor occupancy, and three-dimensional genome architecture govern lineage specification and stage-specific gene expression. Advances in our understanding of the regulatory genome have uncovered how non-coding elements, including enhancers, silencers, and insulators, shape the transcriptional landscape of erythroid cells. These elements work in concert with lineage-determining transcription factors to establish and maintain erythroid identity. Disruption of these epigenetic programs-whether by inherited mutations, somatic alterations, or environmental stress-can lead to a wide range of hematologic disorders. Importantly, this growing knowledge base has opened new therapeutic avenues, enabling the development of precision tools that target regulatory circuits to correct gene expression. These include epigenetic drugs, enhancer-targeted genome editing, and lineage-restricted gene therapies that leverage endogenous regulatory logic. As our understanding of erythroid epigenomics deepens, so too does our ability to design rational, cell-type-specific interventions for red blood cell disorders.