Exploring erythroid cell transcriptomics to understand regulation of fetal hemoglobin expression for advanced sickle cell disease treatment

Abstract Fetal hemoglobin (HbF) modulates the clinical severity of sickle cell disease (SCD) by inhibiting the polymerization of sickle hemoglobin. Elevated HbF levels are associated with milder disease phenotypes, fewer Vaso-occlusive crises, and reduced organ damage. Understanding the molecular regulation of HbF expression is critical for the development of new therapeutic strategies, including pharmacologic agents and gene-based interventions aimed at ameliorating the course of SCD. We investigated transcriptomic expression in erythroid cells during the transition from the neonatal period to early childhood to identify genes associated with HbF regulation. Reticulocyte transcriptomes were compared between samples obtained at birth (cord blood), when HbF levels ranged from 72.6% to 90%, and at 18 months of age (whole blood), when HbF levels declined to 5.9%–10.3%. Reticulocytes were enriched, RNA extracted, and high-throughput RNA sequencing was performed, followed by differential gene expression and network analyses. Analysis of 20 346 genes revealed 1245 differentially expressed genes, of which 631 genes were upregulated in cord blood reticulocytes. The differentially expressed genes were significantly enriched in pathways related to cell signaling, proliferation, differentiation, metabolism, immune functionality, and erythropoiesis. Developmental shifts in the erythroid transcriptome uncover key biological processes that may regulate HbF expression. These findings offer a valuable panel of candidate genes for future functional studies and highlight new potential molecular targets for therapeutic modulation of HbF in sickle cell disease.