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Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.

ABSTRACT: Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and ?-thalassemia1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.

SUBMITTER: Basak A

PROVIDER: S-EPMC7031047 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.

Basak Anindita A Munschauer Mathias M Lareau Caleb A CA Montbleau Kara E KE Ulirsch Jacob C JC Hartigan Christina R CR Schenone Monica M Lian John J Wang Yaomei Y Huang Yumin Y Wu Xianfang X Gehrke Lee L Rice Charles M CM An Xiuli X Christou Helen A HA Mohandas Narla N Carr Steven A SA Chen Jane-Jane JJ Orkin Stuart H SH Lander Eric S ES Sankaran Vijay G VG

Nature genetics 20200120 2

Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and β-thalassemia<sup>1</sup>. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development<sup>2-7</sup>. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. ...[more]

PMID: 31959994

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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.

Dataset Information

Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.

Publications

Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.

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