Activation of γ-globin expression by a common variant disrupting IKAROS-binding motif in β-thalassemia

Hualei Luo; Jueheng Wang; Lang Qin; Xinhua Zhang; Hailiang Liu; Chao Niu; Mengyang Song; Congwen Shao; Peng Xu; Miao Yu; Haokun Zhang; Yuhua Ye; Xiangmin Xu

doi:10.1016/j.jgg.2024.10.015

Volume 52 Issue 2

Feb. 2025

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Article Navigation > Journal of Genetics and Genomics > 2025 > 52(2): 157-167

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Activation of γ-globin expression by a common variant disrupting IKAROS-binding motif in β-thalassemia

doi: 10.1016/j.jgg.2024.10.015

a. Innovation Center for Diagnostics and Treatment of Thalassemia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China;
b. Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China;
c. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 201114, China;
d. Department of Pediatrics, 923rd Hospital of the People's Liberation Army, Nanning, Guangxi 530021, China;
e. Cyrus Tang Medical Institute, National Clinical Research Centre for Hematologic Diseases, Collaborative Innovation Centre of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University Suzhou, Suzhou, Jiangsu 215031, China;
f. State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai 200438, China

Received Date: 2024-08-04
Accepted Date: 2024-10-28
Rev Recd Date: 2024-10-27

Available Online: 2025-07-11

Publish Date: 2024-11-08

Abstract

Abstract

Programmed silencing of γ-globin genes in adult erythropoiesis is mediated by several chromatin remodeling complexes, which determine the stage-specific genome architecture in this region. Identification of cis- or trans-acting mutations contributing to the diverse extent of fetal hemoglobin (Hb F) might illustrate the underlying mechanism of γ-β-globin switching. Here, we recruit a cohort of 1142 β-thalassemia patients and dissect the natural variants in the whole β-globin gene cluster through a targeted next-generation sequencing panel. A previously unreported SNP rs7948668, predicted to disrupt the binding motif of IKAROS as a key component of chromatin remodeling complexes, is identified to be significantly associated with higher levels of Hb F and age at onset. Gene-editing on this SNP leads to the elevation of Hb F in both HUDEP-2 and primary CD34⁺ cells while the extent of elevation is amplified in the context of β-thalassemia mutations, indicating epistasis effects of the SNP in the regulation of Hb F. Finally, we perform ChIP-qPCR and 4C assays to prove that this variant disrupts the binding motif of IKAROS, leading to enhanced competitiveness of HBG promoters to locus control regions. This study highlights the significance of common regulatory SNPs and provides potential targets for treating β-hemoglobinopathy.
- β-thalassemia,
- Fetal hemoglobin,
- Single nucleotide polymorphism,
- IKAROS,
- Locus control region

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References(49)

References

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