Lan, X., Khandros, E., Huang, P., Peslak, S. A., Bhardwaj, S. K., Grevet, J. D., Abdulmalik, O., Wang, H., Keller, C. A., Giardine, B., Baeza, J., Duffner, E. R., El Demerdash, O., Wu, X. S., Vakoc, C. R., Garcia, B. A., Hardison, R. C., Shi, J., Blobel, G. A. (May 2019) The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells. Blood Adv, 3 (10). pp. 1586-1597. ISSN 2473-9529
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Abstract
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.
| Item Type: | Paper |
|---|---|
| Additional Information: | Blood advances |
| Subjects: | Investigative techniques and equipment bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromatin remodeling Investigative techniques and equipment > CRISPR-Cas9 |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matthew Dunn |
| Date: | 28 May 2019 |
| Date Deposited: | 12 Aug 2019 16:25 |
| Last Modified: | 02 Feb 2024 16:31 |
| PMCID: | PMC6538866 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/38205 |
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