The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells.
作者： Xianjiang Lan , Eugene Khandros , Peng Huang , Scott A. Peslak , Saurabh K. Bhardwaj
DOI: 10.1182/BLOODADVANCES.2019032318
关键词: Fetal hemoglobin 、 Ubiquitin ligase complex 、 Cell biology 、 Ubiquitin ligase 、 Globin 、 Biology 、 Repressor 、 Chromatin 、 Transcriptome 、 SPOP
摘要: Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and β-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 (SPOP), substrate adaptor the CUL3 ubiquitin ligase complex, emerged as novel repressor. Depletion SPOP or overexpression dominant negative version significantly raised globin messenger RNA levels minimal detrimental effects on normal erythroid maturation, determined by transcriptome proteome analyses. controls expression independently major transcriptional repressors BCL11A LRF. Finally, inducers cooperate depletion during upregulation. Our study implicates system in controlling human cells may offer therapeutic strategies for treatment β-hemoglobinopathies.
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