The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells

Xianjiang Lan, Eugene Khandros, Peng Huang, Scott A. Peslak, Saurabh K. Bhardwaj, Jeremy D. Grevet, Osheiza Abdulmalik, Hongxin Wang, Cheryl A. Keller, Belinda Giardine, Josue Baeza, Emily R. Duffner, Osama El Demerdash, Xiaoli S. Wu, Christopher R. Vakoc, Benjamin A. Garcia, Ross C. Hardison, Junwei Shi, Gerd A. Blobel

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and b-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 b-hemoglobinopathies.

Original languageEnglish (US)
Pages (from-to)1586-1597
Number of pages12
JournalBlood Advances
Volume3
Issue number10
DOIs
StatePublished - May 28 2019

All Science Journal Classification (ASJC) codes

  • Hematology

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