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Human genetics implicates a BACH2-NRF2 axis in fetal hemoglobin activation

ABSTRACT: Human genetic studies have identified key regulators of fetal hemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances1–6. Yet the mechanisms by which HbF expression is activated remain incompletely understood7. Here, we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,278 individuals that identifies 91 conditionally-independent associations across 12 genomic regions. In one previously uncharacterized associated region, the high-HbF-linked causal variant, rs1010474-C, reduces BACH2 expression and elevates HbF levels. Direct perturbation or inhibition of BACH2 likewise increases HbF expression. Mechanistically, BACH2 restrains activation of the HbF-encoding -globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the -globin genes. Although BACH2 and NRF2 binding motifs in the -globin promoters overlap, they can be selectively edited to activate or repress -globin, respectively, and do so independently of BCL11A. These findings illustrate how human genetic variation continues to advance our understanding of therapeutically-relevant regulatory mechanisms underlying HbF expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345418 | GEO | 2026/08/28

REPOSITORIES: GEO

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