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Peer-reviewedCC BYNature

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

  • C. Guo1,2,3,4
  • Uma P. Arora1,2,3,4
  • Xiaoheng Cheng1,2,3,4
  • Wanying Xu1,2,3,4
  • Liam D. Cato1,2,3,4
  • Rick Li1,2,3,4
  • Henry Y. Lu1,2,3,4
  • Andrew Lee1,2,3,4
  • Fulong Yu1,2,3,4
  • Gaurav Agarwal1,2,3,4
  • Peng Lyu1,2,3,4
  • Tianyi Ye1,2,3,4
42 more authors
  • Mateusz Antoszewski1,2,3,4
  • Mariel Wissmann1,2,3,4
  • Baraka Stewart Mkumbe5,6,7
  • Supachai Ekwattanakit8
  • Patrick Deelen9,10
  • Liberata Mwita11
  • Raphael Zozimus Sangeda11,7
  • Thidarat Suksangpleng8
  • Suchada Riolueang8
  • Paola G. Bronson12
  • Dirk S. Paul13,14
  • Emily Kawabata13
  • William John Astle13,15,16,17
  • François Aguet1
  • Kristin Ardlie1
  • Aitzkoa Lopez de Lapuente Portilla18,19
  • Guolian Kang20
  • Yingze Zhang21
  • Mehdi syed Nouraie21
  • Victor R. Gordeuk22
  • Mark T. Gladwin23
  • Melanie E. Garrett24
  • Allison E. Ashley‐Koch24
  • Marilyn J. Telen24
  • Brian Custer25,26
  • Shannon Kelly27,26
  • Carla Luana Dinardo28,29
  • Éster Cerdeira Sabino29
  • Paula Rodrigues Andrade da Cunha Loureiro30
  • Anna Bárbara Carneiro-Proietti31
  • Cláudia Maximo32
  • Adriana Mendez33
  • Angelika Hammerer‐Lercher33
  • Julie Makani6,7
  • Vivien Sheehan34
  • Mitchell J. Weiss20
  • Lude Franke9,10
  • Björn Nilsson1,18,19
  • Adam S. Butterworth13,14,35,36,17
  • Vip Viprakasit37,8
  • Siana Watoky Nkya6,7,38
  • Vijay G. Sankaran39,40
40 affiliations
  1. 1Broad Institute of MIT and Harvard, Cambridge, MA, USA
  2. 2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  3. 3Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
  4. 4Howard Hughes Medical Institute, Boston, MA, USA
  5. 5Department of Artificial Intelligence and Innovative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
  6. 6Department of Biochemistry, Muhimbili University of Health and Allied Science, Dar es Salaam, Tanzania
  7. 7Sickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
  8. 8Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
  9. 9Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  10. 10Oncode Institute, Amsterdam, The Netherlands
  11. 11Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
  12. 12R&D Translational Biology, Biogen, Cambridge, MA, USA
  13. 13British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  14. 14British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK
  15. 15MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
  16. 16NHS Blood and Transplant, Cambridge, UK
  17. 17National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK
  18. 18Department of Laboratory Medicine, Lund University, Lund, Sweden
  19. 19Lund Stem Cell Center, Lund University, Lund, Sweden
  20. 20St. Jude Children's Research Hospital, Memphis, TN, USA
  21. 21Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
  22. 22Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, IL, USA
  23. 23Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
  24. 24Department of Medicine, Duke University Medical Center, Durham, NC, USA
  25. 25Department of Laboratory Medicine, UCSF, San Francisco, CA, USA
  26. 26Vitalant Research Institute, San Francisco, CA, USA
  27. 27Division of Pediatric Hematology, UCSF Benioff Children's Hospital, Oakland, CA, USA
  28. 28Fundacao Pro-Sangue Hemocentro de Sao Paulo, Sao Paulo, Brazil
  29. 29Institute of Tropical Medicine, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
  30. 30Fundacao Hemope, Recife, Brazil
  31. 31Fundacao Hemominas, Belo Horizonte, Brazil
  32. 32Fundacao Hemorio, Rio de Janeiro, Brazil
  33. 33Institute of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland
  34. 34Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta & Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
  35. 35Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
  36. 36Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
  37. 37Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
  38. 38Tanzania Human Genetics Organisation, Dar es Salaam, Tanzania
  39. 39Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  40. 40Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected]
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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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Cite

BibTeXRIS
BibTeX
@article{guo2026human,
  title = {{Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation}},
  author = {C. Guo and Uma P. Arora and Xiaoheng Cheng and Wanying Xu and Liam D. Cato and Rick Li and Henry Y. Lu and Andrew Lee and Fulong Yu and Gaurav Agarwal and Peng Lyu and Tianyi Ye and Mateusz Antoszewski and Mariel Wissmann and Baraka Stewart Mkumbe and Supachai Ekwattanakit and Patrick Deelen and Liberata Mwita and Raphael Zozimus Sangeda and Thidarat Suksangpleng and Suchada Riolueang and Paola G. Bronson and Dirk S. Paul and Emily Kawabata and William John Astle and François Aguet and Kristin Ardlie and Aitzkoa Lopez de Lapuente Portilla and Guolian Kang and Yingze Zhang and Mehdi syed Nouraie and Victor R. Gordeuk and Mark T. Gladwin and Melanie E. Garrett and Allison E. Ashley‐Koch and Marilyn J. Telen and Brian Custer and Shannon Kelly and Carla Luana Dinardo and Éster Cerdeira Sabino and Paula Rodrigues Andrade da Cunha Loureiro and Anna Bárbara Carneiro-Proietti and Cláudia Maximo and Adriana Mendez and Angelika Hammerer‐Lercher and Julie Makani and Vivien Sheehan and Mitchell J. Weiss and Lude Franke and Björn Nilsson and Adam S. Butterworth and Vip Viprakasit and Siana Watoky Nkya and Vijay G. Sankaran},
  journal = {Nature},
  year = {2026},
  month = sep,
  doi = {10.1038/s41586-026-11113-2},
  url = {https://doi.org/10.1038/s41586-026-11113-2},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation
AU  - C. Guo
AU  - Uma P. Arora
AU  - Xiaoheng Cheng
AU  - Wanying Xu
AU  - Liam D. Cato
AU  - Rick Li
AU  - Henry Y. Lu
AU  - Andrew Lee
AU  - Fulong Yu
AU  - Gaurav Agarwal
AU  - Peng Lyu
AU  - Tianyi Ye
AU  - Mateusz Antoszewski
AU  - Mariel Wissmann
AU  - Baraka Stewart Mkumbe
AU  - Supachai Ekwattanakit
AU  - Patrick Deelen
AU  - Liberata Mwita
AU  - Raphael Zozimus Sangeda
AU  - Thidarat Suksangpleng
AU  - Suchada Riolueang
AU  - Paola G. Bronson
AU  - Dirk S. Paul
AU  - Emily Kawabata
AU  - William John Astle
AU  - François Aguet
AU  - Kristin Ardlie
AU  - Aitzkoa Lopez de Lapuente Portilla
AU  - Guolian Kang
AU  - Yingze Zhang
AU  - Mehdi syed Nouraie
AU  - Victor R. Gordeuk
AU  - Mark T. Gladwin
AU  - Melanie E. Garrett
AU  - Allison E. Ashley‐Koch
AU  - Marilyn J. Telen
AU  - Brian Custer
AU  - Shannon Kelly
AU  - Carla Luana Dinardo
AU  - Éster Cerdeira Sabino
AU  - Paula Rodrigues Andrade da Cunha Loureiro
AU  - Anna Bárbara Carneiro-Proietti
AU  - Cláudia Maximo
AU  - Adriana Mendez
AU  - Angelika Hammerer‐Lercher
AU  - Julie Makani
AU  - Vivien Sheehan
AU  - Mitchell J. Weiss
AU  - Lude Franke
AU  - Björn Nilsson
AU  - Adam S. Butterworth
AU  - Vip Viprakasit
AU  - Siana Watoky Nkya
AU  - Vijay G. Sankaran
PY  - 2026
DA  - 2026/09/30
JO  - Nature
DO  - 10.1038/s41586-026-11113-2
UR  - https://doi.org/10.1038/s41586-026-11113-2
AB  - 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.
SN  - 0028-0836
SN  - 1476-4687
ER  -