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The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic implications for treatment of β-thalassemia and sickle cell anemia, two major global health problems. Although significant progress has been made in our understanding of the molecular mechanism of the fetal-to-adult hemoglobin switch, the mechanism of epigenetic regulation of HbF silencing remains to be fully defined. Here, we performed whole-genome bisulfite sequencing and RNA sequencing analysis of the bone marrow-derived GYPA+ erythroid cells from β-thalassemia-affected individuals with widely varying levels of HbF groups (HbF ≥ 95th percentile or HbF ≤ 5th percentile) to screen epigenetic modulators of HbF and phenotypic diversity of β-thalassemia. We identified an ETS2 repressor factor encoded by ERF, whose promoter hypermethylation and mRNA downregulation are associated with high HbF levels in β-thalassemia. We further observed that hypermethylation of the ERF promoter mediated by enrichment of DNMT3A leads to demethylation of γ-globin genes and attenuation of binding of ERF on the HBG promoter and eventually re-activation of HbF in β-thalassemia. We demonstrated that ERF depletion markedly increased HbF production in human CD34+ erythroid progenitor cells, HUDEP-2 cell lines, and transplanted NCG-Kit-V831M mice. ERF represses γ-globin expression by directly binding to two consensus motifs regulating γ-globin gene expression. Importantly, ERF depletion did not affect maturation of erythroid cells. Identification of alterations in DNA methylation of ERF as a modulator of HbF synthesis opens up therapeutic targets for β-hemoglobinopathies. Copyright © 2021. Published by Elsevier Inc.

Citation

Xiuqin Bao, Xinhua Zhang, Liren Wang, Zhongju Wang, Jin Huang, Qianqian Zhang, Yuhua Ye, Yongqiong Liu, Diyu Chen, Yangjin Zuo, Qifa Liu, Peng Xu, Binbin Huang, Jianpei Fang, Jinquan Lao, Xiaoqin Feng, Yafeng Li, Ryo Kurita, Yukio Nakamura, Weiwei Yu, Cunxiang Ju, Chunbo Huang, Narla Mohandas, Dali Li, Cunyou Zhao, Xiangmin Xu. Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia. American journal of human genetics. 2021 Apr 01;108(4):709-721

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PMID: 33735615

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