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RNA-seq of HBBP1 suppression during HPCs erythroid differentiation

ABSTRACT: As relics emerged in endless evolution, pseudogenes lost their coding potential compared to their protein homologs and are long believed to be functionless and thus evolve under neutrality. However, evidence supporting their functionality is quickly accumulating in recent two decades. Herein, we uncovered the evolution history and the essential role of hemoglobin subunit beta pseudogene 1 (HBBP1), which situates in the middle of fetal (γ) and adult globin (δ/β) genes, in human erythropoiesis. HBBP1 was born in the common ancestor of eutherian mammals and under functional constraint in human populations. Remove of HBBP1 in human embryonic stem cells completely blocked their differentiation to erythroid cells, while erythroid differentiation of hematopoietic stem/progenitor cells was also dramatically impaired after HBBP1 reduction, evidencing HBBP1 was required for human erythropoiesis. Mechanistically, HBBP1 RNA harbored a binding motif of heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), competing for the binding of HNRNPA1 and thus stabilizing the key regulator of erythropoiesis, T-cell acute lymphocytic leukemia 1 (TAL1). Moreover, HBBP1 was remarkably increased in β-thalassemia patients and partially required for their fetal hemoglobin elevation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122524 | GEO | 2021/01/20

REPOSITORIES: GEO

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Project description:Basak A, Munschauer M, Lareau CA, Montbleau KE, Ulirsch JC, Hartigan CR, Schenone M, Lian J, Wang Y, Huang Y, Wu X, Gehrke L, Rice CM, An X, Christou HA, Mohandas N, Carr SA, Orkin SH, Chen JJ, Lander ES, and Sankaran VG. Increased production of the beta-like gamma-globin genes that form fetal hemoglobin can ameliorate the severity of sickle cell disease and beta-thalassemia, the major hemoglobin disorders. BCL11A is a key repressor of the gamma-globin genes and is expressed in a developmental stage-specific manner to regulate the physiologic fetal-to-adult hemoglobin switch. Despite extensive studies, the upstream mechanisms underlying the developmental expression of BCL11A and hemoglobin switching in humans have remained mysterious. Here we show that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. While BCL11A mRNA is comparably expressed at all developmental stages in erythroid cells, robust protein expression only occurs in adult erythroid cells. Importantly, at the earlier stages of development, the observed reduction in protein expression is attributable to decreased synthesis and not increased degradation of BCL11A. While BCL11A protein is not well synthesized at these earlier stages of development, its mRNA curiously continues to be associated with ribosomes. Through unbiased proteomic analyses in erythroid cells, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a reciprocal pattern to BCL11A, directly interacts with ribosomes. We show that the observed suppression of BCL11A protein translation is mediated by LIN28B through a direct interaction with BCL11A mRNA and independent of its role in let-7 microRNA biogenesis. Finally, we show that BCL11A is the major functional target in LIN28B-mediated fetal hemoglobin induction. Our results reveal a previously unappreciated regulatory mechanism underlying human hemoglobin switching and illuminate opportunities for developing improved treatments for sickle cell disease and beta-thalassemia.

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RNA-seq of HBBP1 suppression during HPCs erythroid differentiation

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