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

Ruopeng Feng, Thiyagaraj Mayuranathan, Peng Huang, Phillip A. Doerfler, Yichao Li, Yu Yao, Jingjing Zhang, Lance E. Palmer, Kalin Mayberry, Georgios E. Christakopoulos, Peng Xu, Chunliang Li, Yong Cheng, Gerd A. Blobel, M. Celeste Simon and Mitchell J. Weiss ()
Additional contact information
Ruopeng Feng: St Jude Children’s Research Hospital
Thiyagaraj Mayuranathan: St Jude Children’s Research Hospital
Peng Huang: The Children’s Hospital of Philadelphia
Phillip A. Doerfler: St Jude Children’s Research Hospital
Yichao Li: St Jude Children’s Research Hospital
Yu Yao: St Jude Children’s Research Hospital
Jingjing Zhang: St Jude Children’s Research Hospital
Lance E. Palmer: St Jude Children’s Research Hospital
Kalin Mayberry: St Jude Children’s Research Hospital
Georgios E. Christakopoulos: St Jude Children’s Research Hospital
Peng Xu: St Jude Children’s Research Hospital
Chunliang Li: St Jude Children’s Research Hospital
Yong Cheng: St Jude Children’s Research Hospital
Gerd A. Blobel: The Children’s Hospital of Philadelphia
M. Celeste Simon: University of Pennsylvania
Mitchell J. Weiss: St Jude Children’s Research Hospital

Nature, 2022, vol. 610, issue 7933, 783-790

Abstract: Abstract Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to β-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2β2)1. This process has motivated the development of innovative approaches to treat sickle cell disease and β-thalassaemia by increasing HbF levels in postnatal RBCs2. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05312-w

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