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1.
Blood ; 141(22): 2756-2770, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36893455

RESUMO

The switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA) is a paradigm for developmental gene expression control with relevance to sickle cell disease and ß-thalassemia. Polycomb repressive complex (PRC) proteins regulate this switch, and an inhibitor of PRC2 has entered a clinical trial for HbF activation. Yet, how PRC complexes function in this process, their target genes, and relevant subunit composition are unknown. Here, we identified the PRC1 subunit BMI1 as a novel HbF repressor. We uncovered the RNA binding proteins LIN28B, IGF2BP1, and IGF2BP3 genes as direct BMI1 targets, and demonstrate that they account for the entirety of BMI1's effect on HbF regulation. BMI1 functions as part of the canonical PRC1 (cPRC1) subcomplex as revealed by the physical and functional dissection of BMI1 protein partners. Lastly, we demonstrate that BMI1/cPRC1 acts in concert with PRC2 to repress HbF through the same target genes. Our study illuminates how PRC silences HbF, highlighting an epigenetic mechanism involved in hemoglobin switching.


Assuntos
Hemoglobina Fetal , Complexo Repressor Polycomb 1 , Proteínas do Grupo Polycomb , Hemoglobina Fetal/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo
2.
Blood ; 135(24): 2121-2132, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32299090

RESUMO

Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and ß-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9-guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.


Assuntos
Fator 4 Ativador da Transcrição/genética , Hemoglobina Fetal/genética , Proteínas Repressoras/genética , eIF-2 Quinase/genética , Anemia Falciforme/sangue , Anemia Falciforme/genética , Anemia Falciforme/terapia , Animais , Sistemas CRISPR-Cas , Células Cultivadas , Elementos Facilitadores Genéticos , Eritroblastos/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Especificidade da Espécie , Talassemia beta/sangue , Talassemia beta/genética , Talassemia beta/terapia , gama-Globinas/biossíntese , gama-Globinas/genética
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