VCU Massey Cancer Center, Virginia Commonwealth University, 401 College St, Richmond, VA 23298, USA.
Blood. 2013 Apr 25;121(17):3493-501. doi: 10.1182/blood-2012-11-466227. Epub 2013 Feb 26.
An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate β-type globin gene disorders such as sickle cell anemia and β-thalassemia through activation of the fetal γ-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in γ-globin gene silencing, and Mi2β (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2β relieves γ-globin gene silencing in β-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2β binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for γ-globin gene silencing during β-type globin gene switching. Remarkably, <50% knockdown of Mi2β is sufficient to significantly induce γ-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2β is a potential target for therapeutic induction of fetal hemoglobin.
了解人类胎儿到成人血红蛋白的转换为通过激活胎儿γ-珠蛋白基因来改善β-珠蛋白基因疾病（如镰状细胞贫血和β-地中海贫血）提供了可能性。染色质修饰复合物，包括 MBD2-NuRD 和 GATA-1/FOG-1/NuRD，在γ-珠蛋白基因沉默中起作用，而 Mi2β（CHD4）是 NuRD 复合物的关键组成部分。我们观察到，Mi2β 的敲低可缓解β-YAC 转基因鼠化学诱导二聚体造血细胞和 CD34+祖细胞衍生的人类原发性成人红细胞中的γ-珠蛋白基因沉默。我们表明，Mi2β 独立于 MBD2-NuRD 和 GATA-1/FOG-1/NuRD，直接结合并正向调节 KLF1 和 BCL11A 基因，这些基因编码在β-珠蛋白基因转换过程中对γ-珠蛋白基因沉默至关重要的转录因子。值得注意的是，Mi2β 的敲低<50%足以显著诱导γ-珠蛋白基因表达，而不会破坏原发性人 CD34+祖细胞的红细胞分化。这些结果表明 Mi2β 是治疗性诱导胎儿血红蛋白的潜在靶点。
