Activation of γ-globin expression by hypoxia-inducible factor 1α.

Autor: Feng R; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Mayuranathan T; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Huang P; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Doerfler PA; 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., Yao Y; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Zhang J; 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., Mayberry K; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Christakopoulos GE; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Xu P; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Li C; Department of Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA., Cheng Y; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA., Blobel GA; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Simon MC; Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA., Weiss MJ; Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA. mitch.weiss@stjude.org.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Oct; Vol. 610 (7933), pp. 783-790. Date of Electronic Publication: 2022 Oct 12.
DOI: 10.1038/s41586-022-05312-w
Abstrakt: Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to β-globin, which results in fetal haemoglobin (HbF, α 2 γ 2 ) being gradually replaced by adult haemoglobin (HbA, α 2 β 2 ) 1 . This process has motivated the development of innovative approaches to treat sickle cell disease and β-thalassaemia by increasing HbF levels in postnatal RBCs 2 . Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR-Cas9 screen for ubiquitin-proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel-Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor 1α (HIF1α) 3,4 , to induce γ-globin gene transcription. Mechanistically, HIF1α-HIF1β heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7 kb downstream of the tandem γ-globin genes HBG1 and HBG2. This was followed by the recruitment of transcriptional activators, chromatin opening and increased long-range interactions between the γ-globin genes and their upstream enhancer. Similar induction of HbF occurred with hypoxia or with inhibition of prolyl hydroxylase domain enzymes that target HIF1α for ubiquitination by the VHL E3 ubiquitin ligase. Our findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during stress erythropoiesis and suggest a new therapeutic approach for β-haemoglobinopathies.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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