Multi-Omics Analysis in β-Thalassemia Using an Gene-Knockout Human Erythroid Progenitor Cell Model

β-thalassemia is a hematologic disease that may be associated with significant morbidity and mortality. Increased expression of can ameliorate the severity of β-thalassemia. Compared to the unaffected population, some β-thalassemia patients display elevated expression levels in their red blood cells. However, the magnitude of up-regulation does not reach the threshold of self-healing, and thus, the molecular mechanism underlying expression in the context of -deficiency requires further elucidation. Here, we performed a multi-omics study examining chromatin accessibility, transcriptome, proteome, and phosphorylation patterns in the homozygous knockout of the HUDEP2 cell line (HBB-KO). We found that up-regulation of in HBB-KO cells was not induced by the H3K4me3-mediated genetic compensation response. Deletion of in human erythroid progenitor cells resulted in increased ROS levels and production of oxidative stress, which led to an increased rate of apoptosis. Furthermore, in response to oxidative stress, slower cell cycle progression and proliferation were observed. In addition, stress erythropoiesis was initiated leading to increased intracellular expression. This molecular model was also validated in the single-cell transcriptome of hematopoietic stem cells from β-hemoglobinopathy patients. These findings further the understanding of gene regulatory networks and provide novel clinical insights into β-thalassemia phenotypic diversity.