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In β‑thalassemia, excessive α‑globin chain impedes the normal development of red blood cells resulting in anemia. Numerous miRNAs, including miR‑6747‑3p, are aberrantly expressed in β‑thalassemia major (β‑TM), but there are no reports on the mechanism of miR‑6747‑3p in regulating red blood cell lineage development and fetal hemoglobin (HbF) expression. In the present study, RT‑qPCR was utilized to confirm miR‑6747‑3p expression in patients with β‑TM and the healthy controls. Electrotransfection was employed to introduce the miR‑6747‑3p mimic and inhibitor in both HUDEP‑2 and K562 cells, and red blood cell lineage development was evaluated by CCK‑8 assay, flow cytometry, Wright‑Giemsa staining and Benzidine blue staining. B‑cell lymphoma/leukemia 11A (BCL11A) was selected as a candidate target gene of miR‑6747‑3p for further validation through FISH assay, dual luciferase assay and Western blotting. The results indicated that miR‑6747‑3p expression was notably higher in patients with β‑TM compared with healthy controls and was positively related to HbF levels. Functionally, miR‑6747‑3p overexpression resulted in the hindrance of cell proliferation, promotion of cell apoptosis, facilitation of cellular erythroid differentiation and γ‑globin expression in HUDEP‑2 and K562 cells. Mechanistically, miR‑6747‑3p could specifically bind to the 546‑552 loci of BCL11A 3'‑UTR and induce γ‑globin expression. These data indicate that upregulation of miR‑6747‑3p affects red blood cell lineage development and induces HbF expression by targeting BCL11A in β‑thalassemia, highlighting miR‑6747‑3p as a potential molecular target for β‑thalassemia therapy.

Activating transcription factor 4 (ATF4) is a fundamental basic region/leucine zipper transcription factor, responds to various stress signals, and plays crucial roles in normal metabolic and stress response processes. Although its functions in human health and disease are not completely understood, compelling evidence underscores ATF4 is indispensable for multiple stages and lineages of erythroid development, including the regulation of fetal liver hematopoietic stem cells, induction of terminal erythroid differentiation, and maintenance of erythroid homeostasis. β -Thalassemia is a blood disorder arising from mutations in the β -globin gene. Reactivating the expression of the γ -globin gene in adult patients has emerged as a promising therapeutic strategy for ameliorating clinical symptoms associated with β -thalassemia. Recent research has suggested that ATF4 contributes to decreased fetal hemoglobin (HbF) level through its binding to potent negative regulators of HbF, such as BCL11A and MYB. Notably, evidence also suggests a contrasting outcome where increased ATF4 protein levels are associated with enhanced HbF at the transcriptional level. Consequently, the identification of mechanisms that modulate ATF4-mediated γ -globin transcription and its effects on erythroid development may unveil novel targets for β -thalassemia treatment., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In eukaryotic RNA, N6‐methyladenosine (m6A) is a prevalent form of methylation modification. The m6A modification process is reversible and dynamic, written by m6A methyltransferase complex, erased by m6A demethylase, and recognized by m6A binding proteins. Through mediating RNA stability, decay, alternative splicing, and translation processes, m6A modification regulates gene expression at the post‐transcriptional level. Erythropoiesis is the process of hematopoietic stem cells undergoing proliferation, a series of differentiation and maturation to form red blood cells (RBCs). Thalassemia is a common monogenic disease characterized by excessive production of ineffective RBCs in the peripheral circulation, resulting in hemolytic anemia. Increasing evidence suggests that m6A modification plays a crucial role in erythropoiesis. In this review, we comprehensively summarize the function of m6A modification in erythropoiesis and further generalize the mechanism of m6A modification regulating ineffective erythropoiesis and fetal hemoglobin expression. The purpose is to improve the understanding of the pathogenesis of erythroid dysplasia and offer new perspectives for the diagnosis and treatment of thalassemia. [ABSTRACT FROM AUTHOR]

Background: The B cell CLL/lymphoma 11A (BCL11A) is a key regulator of hemoglobin switching in β-thalassemia (β-thal). Previous study has suggested that dysregulated microRNAs are involved in the regulation of BCL11A expression. The aim of this study was to investigate the clinical value of hsa-miR-190b-5p in β-thal, and to confirm the regulatory effect of hsa-miR-190b-5p on BCL11A expression. Methods: The peripheral blood of 25 pediatric β-thal patients and 25 healthy controls were selected, and qRT-PCR was used to analyze the levels of hsa-miR-190b-5p and BCL11A mRNA. The relationship between hsa-miR-190b-5p expression and hematological parameters was assessed by Pearson's correlation test. The diagnostic power of hsa-miR-190b-5p was evaluated by ROC curves analysis. The direct integration between hsa-miR-190b-5p and BCL11A 3'-UTR was confirmed by luciferase reporter assay. Results: Hsa-miR-190b-5p expression in pediatric β-thal was upregulated, and negatively correlated with the MCH and HbA levels, but positively correlated with the HbF level. Hsa-miR-190b-5p showed a good diagnostic capability for pediatric β-thal equivalent to that of HbA2 (AUC: 0.760 vs. 0.758). Moreover, the levels of BCL11A mRNA in pediatric β-thal were decreased, and hsa-miR-190b-5p had a negative correlation with BCL11A mRNA expression (r = -0.403). BCL11A was a target gene of hsa-miR-190b-5p. The mRNA and protein levels of BCL11A were diminished by introduction of hsa-miR-190b-5p, whereas its expression was upregulated by knockdown of hsa-miR-190b-5p. Conclusions: Hsa-miR-190b-5p expression was upregulated in pediatric β-thal and might be an effective diagnostic biomarker. BCL11A was negatively regulated by hsa-miR-190b-5p, which might provide new target for the treatment of pediatric β-thal. [ABSTRACT FROM AUTHOR]