Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin.

Autor: Doerfler PA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Feng R; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Li Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Palmer LE; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Porter SN; Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA., Bell HW; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia., Crossley M; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia., Pruett-Miller SM; Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA., Cheng Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Weiss MJ; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. mitch.weiss@stjude.org.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2021 Aug; Vol. 53 (8), pp. 1177-1186. Date of Electronic Publication: 2021 Aug 02.
DOI: 10.1038/s41588-021-00904-0
Abstrakt: Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-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.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
Externí odkaz: