Genome-Wide Analysis Identifies BACH2 as Potential Fetal Hemoglobin Activation Target
This pathway, which the authors dub the “BACH2-NRF2 axis,” is independent of the well-known BCL11A transcription regulator, the target of the approved cell therapy Casgevy for sickle cell disease (SCD). The post Genome-Wide Analysis Identifies BACH2 as Potential Fetal Hemoglobin Activation Target appeared first on GEN - Genetic Engineering and Biotechnology News .
In a groundbreaking genome-wide meta-analysis, researchers at Boston Children's Hospital and the Broad Institute, led by Vijay G. Sankaran, MD, PhD, have discovered a novel regulatory pathway known as the "BACH2-NRF2 axis" that activates fetal hemoglobin (HbF) expression. This pathway, distinct from the well-known BCL11A transcription regulator, has the potential to become a therapeutic target for sickle cell disease (SCD) and thalassemia.
The findings are published in the journal Nature. For decades, scientists have been exploring the fetal-to-adult hemoglobin switch as a therapeutic avenue for SCD and thalassemia. BCL11A, identified almost 20 years ago, has been a key regulator of this switch. In their study, Sankaran's team analyzed a vast amount of genome-wide association study (GWAS) data from over 28,000 individuals across European, African, and Asian populations.
One of the strongest signals identified a novel regulatory circuit—the BACH2-NRF2 axis—that directly governs γ-globin gene expression. The team discovered that BACH2, a known transcription regulator, reduces expression of BACH2 in erythroid progenitor cells, leading to increased γ-globin transcription and HbF production. They also confirmed that BACH2 functions as a direct repressor at the γ-globin promoter and locus control region LCR, allowing NRF2 to bind and activate γ-globin transcription when BACH2 is lost or inhibited.
The study further revealed that the BACH2-NRF2 axis operates independently of BCL11A, suggesting the possibility of combining therapeutic strategies targeting both pathways for SCD and β-thalassemia treatment.
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