Gene expression changes in sickle cell reticulocytes and their clinical associations

Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR = 2.9, P = 0.00063) and annotation keyword ubiquitin-dependent protein catabolic process, protein ubiquitination, and protein polyubiquitination (OR = 4.2, P = 7.5 x 10(-5)). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR = 1.7, P = 3.9 x 10(-5)). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations.

Automated summary

The transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their impact on the disease remain unclear. Comparison between hemoglobin SS reticulocytes and non-anemic hemoglobin AA controls revealed 1226 differentially expressed genes. Analysis of these genes in hemoglobin AA erythroblasts indicated enhanced terminal differentiation in early erythroblasts in SCA. A comparison with Chuvash erythrocytosis identified 453 SCA-specific changes associated with compensatory erythropoiesis. Additionally, erythroid gene expression in peripheral blood mononuclear cells (PBMCs) from SCA patients showed an enrichment of genes related to the ubiquitin-dependent protein catabolic process. The expression of one of these genes, LNX2, was associated with severe pain episodes in SCA patients.