論文 - 詳細
| RRC ID | 77263 |
|---|---|
| 著者 | Lan X, Khandros E, Huang P, Peslak SA, Bhardwaj SK, Grevet JD, Abdulmalik O, Wang H, Keller CA, Giardine B, Baeza J, Duffner ER, El Demerdash O, Wu XS, Vakoc CR, Garcia BA, Hardison RC, Shi J, Blobel GA. |
| タイトル | The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells. |
| ジャーナル | Blood Adv |
| 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. |
| 巻・号 | 3(10) |
| ページ | 1586-1597 |
| 公開日 | 2019-5-28 |
| DOI | 10.1182/bloodadvances.2019032318 |
| PII | bloodadvances.2019032318 |
| PMID | 31126914 |
| PMC | PMC6538866 |
| MeSH | Adult Erythroid Cells / metabolism* Female Fetal Hemoglobin / genetics* Humans Male Nuclear Proteins / genetics Nuclear Proteins / metabolism* Repressor Proteins / genetics Repressor Proteins / metabolism* Ubiquitin-Protein Ligases / metabolism* Young Adult |
| IF | 4.91 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |