期刊
BLOOD ADVANCES
卷 3, 期 10, 页码 1586-1597出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2019032318
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资金
- National Institutes of Health, National Institute of General Medical Sciences [T32GM008216, R01-GM110174]
- National Institute of Diabetes and Digestive and Kidney Diseases [1F30DK107055-01, R56DK065806, 5R37DK058044]
- National Human Genome Research Institute [U54HG006998]
- National Heart, Lung, and Blood Institute [5R01HL119479]
- National Institute of Allergy and Infectious Diseases [R01-AI118891]
- US Department of Defense [W81XWH-113-1-0426]
- Cold Spring Harbor Laboratory
- DiGaetano family
Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and beta-thalassemia. To identify new HbF regulators that might be amenable to pharmacologic control, we screened a protein domain-focused CRISPR-Cas9 library targeting chromatin regulators, including BTB domain-containing proteins. Speckle-type POZ protein (SPOP), a substrate adaptor of the CUL3 ubiquitin ligase complex, emerged as a novel HbF repressor. Depletion of SPOP or overexpression of a dominant negative version significantly raised fetal globin messenger RNA and protein levels with minimal detrimental effects on normal erythroid maturation, as determined by transcriptome and proteome analyses. SPOP controls HbF expression independently of the major transcriptional HbF repressors BCL11A and LRF. Finally, pharmacologic HbF inducers cooperate with SPOP depletion during HbF upregulation. Our study implicates SPOP and the CUL3 ubiquitin ligase system in controlling HbF production in human erythroid cells and may offer new therapeutic strategies for the treatment of beta-hemoglobinopathies.
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