红系特异转录因子KLF1是红细胞发育中关键的细胞因子，直接参与调控了胎儿血红蛋白（HbF）向成人血红蛋白（HbA）转化过程。β地中海贫血（β地贫）患者的临床表型从中间型到重型存在很大差异，由于HbA的生成障碍，HbF的表达水平成为影响β地贫临床表型严重性的主要遗传因素。前期研究中我们已报道：人类KLF1基因变异导致的单倍型不足可以使HbF持续表达，进而缓解β地贫患者的临床表型，这提示KLF1基因对表型的影响存在剂量效应。我们前期研究证明KLF1基因启动子区域甲基化对其表达起到抑制作用，此外预实验初步发现2个miRNA对KLF1表达有抑制作用。因此本研究将以KLF1表达负调控机制为切入点，分析其对β地贫患者临床表型的修饰作用，为解释β地贫临床表型多样性提供表观遗传学基础证据，为β地贫临床诊治、发病机制和遗传咨询提供新的遗传知识和依据。

Erythroid Krüppel-like factor KLF1 is a master regulator of erythropoiesis and has recently emerged as one of the key regulators of the γ- to β-globin gene switch. Due to little or no production of HbA, expression of HbF becomes the major genetic factor altering the severity of β-thalassemia, which may accounts for the phenotypic diversity of β-thalassemia. Previously, we have reported that haploinsufficiency of KLF1 results in significant increases in fetal hemoglobin (HbF) levels and attenuation of the severity of β-thalassemia, which reflects the underlying dose-respond effect between KLF1 gene expression and phenotype of β-thalassemia. Recently, we proved that the transcriptional activity of KLF1 was inhibited by promoter DNA methylation. In addition, we conducted pre-tests and found that two miRNAs can inhibit KLF1 expression. Given to these findings, we aim to find KLF1 negative regulatory factors and analyze its effects on phenotypic modification in patients with β-thalassemia. It may provide a rationale for epigenetics in phenotypic diversity of β-thalassemia, and new genetic information and data for treatment, pathogenesis as well as genetic counseling in β-thalassemia.