期刊
BLOOD
卷 133, 期 8, 页码 852-856出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-07-863951
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资金
- Australian National Health and Medical Research Council [APP1098391]
- Australian Postgraduate Award
- University International Postgraduate Award
- UNSW Sydney Scientia Fellowship
beta-hemoglobinopathies, such as sickle cell disease and beta-thalassemia, result from mutations in the adult beta-globin gene. Reactivating the developmentally silenced fetal gamma-globin gene elevates fetal hemoglobin levels and ameliorates symptoms of beta-hemoglobinopathies. The continued expression of fetal gamma-globin into adulthood occurs naturally in a genetic condition termed hereditary persistence of fetal hemoglobin (HPFH). Point mutations in the fetal gamma-globin proximal promoter can cause HPFH. The -113A>G HPFH mutation falls within the 2115 cluster of HPFH mutations, a binding site for the fetal globin repressor BCL11A. We demonstrate that the -113A>G HPFH mutation, unlike other mutations in the cluster, does not disrupt BCL11A binding but rather creates a de novo binding site for the transcriptional activator GATA1. Introduction of the -113A>G HPFH mutation into erythroid cells using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system increases GATA1 binding and elevates fetal globin levels. These results reveal the mechanism by which the -113A>G HPFH mutation elevates fetal globin and demonstrate the sensitivity of the fetal globin promoter to point mutations that often disrupt repressor binding sites but here create a de novo site for an erythroid activator.
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