Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation

Abstract Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances 1–8 . Yet the mechanisms by which HbF expression is activated remain incompletely understood 9 . Here we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 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 γ-globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the γ-globin genes. Although BACH2 and NRF2 binding motifs in the γ-globin promoters overlap, they can be selectively edited to activate or repress γ-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.

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Publication Details

Journal
Nature
Published
2026-09-30
DOI
https://doi.org/10.1038/s41586-026-11113-2
Primary Topic
Hemoglobinopathies and Related Disorders
Type
article
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article

Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation

Liam D. Cato, Vijay G. Sankaran, Henry Y. Lu, William John Astle et al.
Nature
Hemoglobinopathies and Related Disorders
article

Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation

Liam D. Cato, Vijay G. Sankaran, Henry Y. Lu, William John Astle, Mark T. Gladwin, Rick Li, Victor R. Gordeuk, Baraka Stewart Mkumbe, Kristin Ardlie, Dirk S. Paul, Patrick Deelen, Xiaoheng Cheng, Aitzkoa Lopez de Lapuente Portilla, Tianyi Ye, Carla Luana Dinardo, Suchada Riolueang, Adriana Mendez, Siana Watoky Nkya, Uma P. Arora, Vivien Sheehan, Brian Custer, Gaurav Agarwal, Mateusz Antoszewski, Melanie E. Garrett, Raphael Zozimus Sangeda, Paola G. Bronson, Mitchell J. Weiss, Björn Nilsson, Angelika Hammerer‐Lercher, Marilyn J. Telen, Mehdi syed Nouraie, Allison E. Ashley‐Koch, Guolian Kang, Supachai Ekwattanakit, Éster Cerdeira Sabino, Thidarat Suksangpleng, Vip Viprakasit, Lude Franke, Emily Kawabata, Chun-Jie Guo, Adam S. Butterworth, Mariel Wissmann, Wanying Xu, Andrew Lee, Yingze Zhang, Peng Lyu, Paula Loureiro, Shannon Kelly, Francois Aguet, Anna Bárbara Carneiro-Proietti, Cláudia Maximo, Liberata Mwita, Fulong Yu, Julie Makani
article en

Abstract

Abstract Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances 1–8 . Yet the mechanisms by which HbF expression is activated remain incompletely understood 9 . Here we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 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 γ-globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the γ-globin genes. Although BACH2 and NRF2 binding motifs in the γ-globin promoters overlap, they can be selectively edited to activate or repress γ-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.

Nature
Broad Institute (US), University of Maryland, Baltimore (US), Boston Children's Hospital (US), Biogen (United States) (US), NHS Blood and Transplant (GB), St. Jude Children's Research Hospital (US), Siriraj Hospital (TH), University Medical Center Groningen (NL), Howard Hughes Medical Institute (US), Harvard University (US), Muhimbili University of Health and Allied Sciences (TZ), University of Groningen (NL), University of Pittsburgh (US), Universidade de São Paulo (BR), University of California, San Francisco (US), Lund University (SE), Tohoku University (JP), University of Cambridge (GB), Mahidol University (TH), National Institute for Health and Care Research (GB), University of Illinois Chicago (US), Hemorio (BR), Oncode Institute (NL), Dana-Farber Cancer Institute (US), Duke Medical Center (US), MRC Biostatistics Unit (GB), UCSF Benioff Children's Hospital (US), Fundação Hemopa (BR), Health Data Research UK (GB), Children's Healthcare of Atlanta (US), Fundação Centro de Hematologia e Hemoterapia de Minas Gerais (BR), Harvard Stem Cell Institute (US), Fundação Pró-Sangue Hemocentro de São Paulo (BR), Kantonsspital Aarau (CH), Vitalant Research Institute (US)
Good health and well-being
Openalex Percentile: Top 12%
Hemoglobinopathies and Related Disorders
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