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

Authors

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

Published in

Nature. Sep 30, 2026. Epub Sep 30, 2026.

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 understood⁹. 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.

PMID:
42816612
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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