美国波士顿哈佛医学院Vijay G. Sankaran研究团队取得一项新突破。他们的最新研究探明了人类遗传学暗示BACH2-NRF2轴与胎儿血红蛋白激活有关。相关论文于2026年9月30日发表在《自然》杂志上。

人类遗传学研究已鉴定出胎儿血红蛋白（HbF）表达的关键调控因子，包括BCL11A，从而带来了治疗进展。然而，HbF表达被激活的机制仍不完全清楚。在此，研究人员对28,279名个体的HbF水平开展了一项大型多祖先全基因组关联研究，鉴定出跨12个基因组区域的91个条件独立关联。在一个此前未表征的关联区域中，与高HbF相关的因果变异rs1010474-C降低BACH2表达并升高HbF水平。直接扰动或抑制BACH2同样增加HbF表达。机制上，BACH2抑制编码HbF的γ-珠蛋白基因的激活，而BACH2缺失增强NRF2染色质占据，并促进γ-珠蛋白基因处激活灶的形成。尽管γ-珠蛋白启动子中BACH2和NRF2结合基序重叠，但它们可以被选择性编辑以分别激活或抑制γ-珠蛋白，并且这一过程不依赖于BCL11A。这些发现说明了人类遗传变异如何继续推进研究人员对HbF表达背后具有治疗相关性的调控机制的理解。

附：英文原文

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

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

Issue&Volume: 2026-09-30

Abstract: Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances1,2,3,4,5,6,7,8. 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.

DOI: 10.1038/s41586-026-11113-2

Source: https://www.nature.com/articles/s41586-026-11113-2