A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression
A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression
复制标题
一种遗传变异通过表观遗传介导的人类胎儿血红蛋白表达的升高来改善β地中海贫血的严重程度
DOI：
10.1016/j.ajhg.2017.05.012
复制
发表时间：
2017-07-06
影响因子：
9.8
通讯作者：
Xu, Xiangmin
中科院分区：
文献类型：
--
作者：
Chen, Diyu;Zuo, Yangjin;Xu, Xiangmin
延迟的胎儿至成人血红蛋白（Hb）转换可改善β-地中海贫血和镰状细胞病的严重程度。开关的表观遗传失调的分子机制尚不清楚。为了探索潜在的顺式变异体的血红蛋白开关，我们系统地分析了一个80 kb的区域跨越β珠蛋白簇使用捕获为基础的下一代测序的1142中国β地中海贫血的人，并确定了31个胎儿血红蛋白（HbF）相关的单倍型的选择28个标签的调节单核苷酸多态性（rSNPs）在7个连锁不平衡（LD）块。来自血红蛋白γ亚基1（HBG 1）近端启动子中LD块5的Ly 1抗体反应性（LYAR）结合基序破坏性rSNP rs368698783（G/A）被发现是表观遗传介导的变异依赖性HbF升高的β地中海贫血临床严重程度的重要预测因子。我们发现，在来自中国南方和泰国的总共2,738名患者中，这种rSNP占β-血红蛋白病患者的41.6%，作为改善因素。我们发现，rSNP的次要等位基因触发LYAR和来自HBG启动子的两个抑制性表观遗传调节因子DNA甲基转移酶3 α（DNMT 3A）和蛋白质精氨酸甲基转移酶5（PRMT 5）的衰减，通过促进β-地中海贫血患者红系祖细胞中HBG核心启动子CpG位点的去甲基化来介导等位基因偏倚的γ-珠蛋白升高。目前的研究表明，这种常见的rSNP在近端A γ启动子是一个主要的遗传修饰剂，能够改善严重的地中海贫血的严重程度，通过表观遗传介导的调节延迟胎儿到成人血红蛋白开关，并提供了潜在的治疗β-血红蛋白病的目标。
A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of beta-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the beta-globin cluster using capture-based next-generation sequencing of 1142 Chinese beta-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for beta-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of beta-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased gamma-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from beta-thalassemia persons. The present study demonstrates that this common rSNP in the proximal A gamma-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of beta-hemoglobinopathy.