Transcriptomic profiling of an ex vivo model of erythropoiesis uncovers potential genes and pathways involved into the pathogenesis of sickle cell disease

We characterized the transcriptional profiles of erythroid cells differentiated from peripheral blood mononuclear cells (PBMCs) from peripheral blood collected from patients diagnosed with Sickle Cell Disease (SCD), which have been treated with Hydroxyurea (HU) in comparison to untreated SCD patients and healthy controls (HC) using bulk RNAseq. We identified 1398 differentially expressed genes (DEGs) in SCD non-treated-derived erythroid cells and 495 DEGs in SCD HU-treated patient-derived erythroid cells compared to HC. We found biological processes such as oxidative phosphorylation pathway, proteasome, autophagy, natural killer cell (NK) cytotoxicity, adaptive immune response or inflammatory response to be significantly enriched in our patient study groups by using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Our findings collectively suggest different as well as common molecular signatures between our groups. We could validate 12 of our top DEGs in treated patients by qRT-PCR. We found similar regulation patterns when comparing the mRNA levels of mutS homolog 5-Suppressor APC Domain Containing 1 (MSH5-SAPCD1), G protein subunit gamma 4 (GNG4), stabilin 1/ clever-1 (STAB1) and Fas Binding Factor 1 (FBF1) from the bone marrow cells and spleen tissue from the Berkely SCD mouse model to the expressions observed in the transcriptome of our ex-vivo patient-derived erythropoiesis model.