Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milano, Italy.
Istituto di Ricerca Genetica e Biomedica del Consiglio Nazionale delle Ricerche, Cagliari, Italy.
Haematologica. 2021 Feb 1;106(2):474-482. doi: 10.3324/haematol.2019.241224.
The human fetal γ-globin gene is repressed in the adult stage through complex regulatory mechanisms involving transcription factors and epigenetic modifiers. Reversing γ-globin repression, or maintaining its expression by manipulating regulatory mechanisms, has become a major clinical goal in the treatment of β-hemoglobinopathies. Here, we identify the orphan nuclear receptor Coup-TFII (NR2F2/ARP-1) as an embryonic/fetal stage activator of γ-globin expression. We show that Coup-TFII is expressed in early erythropoiesis of yolk sac origin, together with embryonic/fetal globins. When overexpressed in adult cells (including peripheral blood cells from human healthy donors and β039 thalassemic patients) Coup-TFII activates the embryonic/fetal globins genes, overcoming the repression imposed by the adult erythroid environment. Conversely, the knock-out of Coup-TFII increases the β/γ+β globin ratio. Molecular analysis indicates that Coup-TFII binds in vivo to the β-locus and contributes to its conformation. Overall, our data identify Coup-TFII as a specific activator of the γ-globin gene.
人类胎儿γ-珠蛋白基因在成人阶段通过涉及转录因子和表观遗传修饰物的复杂调控机制被抑制。通过操纵调控机制逆转γ-珠蛋白的抑制或维持其表达，已成为治疗β-地中海贫血症的主要临床目标。在这里，我们确定孤儿核受体 Coup-TFII（NR2F2/ARP-1）为γ-珠蛋白表达的胚胎/胎儿阶段激活剂。我们表明 Coup-TFII 与胚胎/胎儿珠蛋白一起在卵黄囊来源的早期红细胞生成中表达。当在成人细胞（包括来自健康供体和β039 地中海贫血患者的外周血）中过表达时，Coup-TFII 激活胚胎/胎儿珠蛋白基因，克服了成人红细胞环境施加的抑制。相反，Coup-TFII 的敲除会增加β/γ+β 珠蛋白的比值。分子分析表明 Coup-TFII 在体内与β 基因座结合，并有助于其构象。总体而言，我们的数据将 Coup-TFII 鉴定为γ-珠蛋白基因的特异性激活剂。
