Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin.
Nat Genet
; 53(8): 1177-1186, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-34341563
ABSTRACT
Hereditary persistence of fetal hemoglobin (HPFH) ameliorates ß-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to ß-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hemoglobina Fetal
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Fator de Ligação a CCAAT
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Fator de Transcrição GATA1
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Gama-Globinas
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos