The E3 Ligase Adaptor Molecule SPOP Regulates Fetal Hemoglobin Levels in Adult Erythroid Cells

Overview

Journal Blood Adv

Specialty Hematology

Date 2019 May 26

PMID 31126914

Citations 14

Authors

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

Affiliations

Soon will be listed here.

Abstract

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 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 β-hemoglobinopathies.

Citing Articles

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