Human genetics implicates a BACH2-NRF2 axis in fetal haemoglobin activation.

A BACH2-NRF2 regulatory axis is identified as a key modulator of fetal hemoglobin activation, with a specific variant reducing BACH2 expression to increase HbF levels.

• Why it matters: Understanding the mechanisms controlling fetal hemoglobin is crucial for developing therapies for hemoglobinopathies, yet these pathways are not fully elucidated.
• What they did: A large multi-ancestry genome-wide association study of 28,279 individuals uncovered 91 genetic associations, including a variant that decreases BACH2 expression and raises HbF, with functional experiments confirming BACH2's inhibitory role and NRF2's activating role at the γ-globin genes.
• The result: These insights reveal how genetic variation influences HbF regulation through BACH2 and NRF2, providing potential targets for therapeutic intervention independent of known regulators like BCL11A.