APA
Click to copy
Mayuranathan, T., Newby, G. A., Feng, R., Yao, Y., Mayberry, K., Lazzarotto, C., … Yen, J. S. (2023). Potent and uniform fetal hemoglobin induction via base editing. Nature Genetics.
Chicago/Turabian
Click to copy
Mayuranathan, Thiyagaraj, Gregory A. Newby, Ruopeng Feng, Yu Yao, Kalin Mayberry, C. Lazzarotto, Yichao Li, et al. “Potent and Uniform Fetal Hemoglobin Induction via Base Editing.” Nature Genetics (2023).
MLA
Click to copy
Mayuranathan, Thiyagaraj, et al. “Potent and Uniform Fetal Hemoglobin Induction via Base Editing.” Nature Genetics, 2023.
BibTeX Click to copy
@article{thiyagaraj2023a,
title = {Potent and uniform fetal hemoglobin induction via base editing},
year = {2023},
journal = {Nature Genetics},
author = {Mayuranathan, Thiyagaraj and Newby, Gregory A. and Feng, Ruopeng and Yao, Yu and Mayberry, Kalin and Lazzarotto, C. and Li, Yichao and Levine, Rachel M. and Nimmagadda, Nikitha and Dempsey, Erin and Kang, G. and Porter, Shaina N. and Doerfler, Phillip A. and Zhang, Jingjing and Jang, YoonJeong and Chen, Jingjing and Bell, Henry W. and Crossley, M. and Bhoopalan, S. and Sharma, Akshay and Tisdale, J. and Pruett-Miller, S. and Cheng, Yong and Tsai, S. and Liu, David R. and Weiss, M. and Yen, Jonathan S.}
}
A comparison of fetal hemoglobin gene editing strategies using human sickle cell disease donor cells and in vivo transplantation finds that adenine base editing of the –175A>G site in the γ-globin gene promoters results in durable and potent expression. Inducing fetal hemoglobin (HbF) in red blood cells can alleviate β-thalassemia and sickle cell disease. We compared five strategies in CD34^+ hematopoietic stem and progenitor cells, using either Cas9 nuclease or adenine base editors. The most potent modification was adenine base editor generation of γ-globin –175A>G. Homozygous –175A>G edited erythroid colonies expressed 81 ± 7% HbF versus 17 ± 11% in unedited controls, whereas HbF levels were lower and more variable for two Cas9 strategies targeting a BCL11A binding motif in the γ-globin promoter or a BCL11A erythroid enhancer. The –175A>G base edit also induced HbF more potently than a Cas9 approach in red blood cells generated after transplantation of CD34^+ hematopoietic stem and progenitor cells into mice. Our data suggest a strategy for potent, uniform induction of HbF and provide insights into γ-globin gene regulation. More generally, we demonstrate that diverse indels generated by Cas9 can cause unexpected phenotypic variation that can be circumvented by base editing.