Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

作者：Bao, Xiuqin; Zhang, Xinhua; Wang, Liren; Wang, Zhongju; Huang, Jin; Zhang, Qianqian; Ye, Yuhua; Liu, Yongqiong; Chen, Diyu; Zuo, Yangjin; Liu, Qifa; Xu, Peng; Huang, Binbin; Fang, Jianpei; Lao, Jinquan; Feng, Xiaoqin; Li, Yafeng; Kurita, Ryo; Nakamura, Yukio; Yu, Weiwei; Ju, Cunxiang; Huang, Chunbo; Mohandas, Narla; Li, Dali; Zhao, Cunyou; Xu, Xiangmin

来源：American Journal of Human Genetics, 2021, 108(4): 709-721.

DOI：10.1016/j.ajhg.2021.03.005

• FETAL-HEMOGLOBIN
• WIDE ASSOCIATION
• GENOME
• GENE
• REGULATOR
• MODIFIERS
• SEVERITY
• PROTEIN
• VARIANT
• COMMON

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 beta-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 GYPAthorn erythroid cells from beta-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 beta-thalassemia. We identified an ETS2 repressor factor encoded by ERF, whose promoter hypermethylation and mRNA down-regulation are associated with high HbF levels in beta-thalassemia. We further observed that hypermethylation of the ERF promoter mediated by enrichment of DNMT3A leads to demethylation of gamma-globin genes and attenuation of binding of ERF on the HBG promoter and eventually re-activation of HbF in beta-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 gamma-globin expression by directly binding to two consensus motifs regulating gamma-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 beta-hemoglobinopathies.

• 单位
  苏州大学; 1; 南方医科大学; 中山大学