School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia.
Research and Development Department, Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan.
Nat Genet. 2018 Apr;50(4):498-503. doi: 10.1038/s41588-018-0085-0. Epub 2018 Apr 2.
β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia result from mutations in the adult HBB (β-globin) gene. Reactivating the developmentally silenced fetal HBG1 and HBG2 (γ-globin) genes is a therapeutic goal for treating SCD and β-thalassemia . Some forms of hereditary persistence of fetal hemoglobin (HPFH), a rare benign condition in which individuals express the γ-globin gene throughout adulthood, are caused by point mutations in the γ-globin gene promoter at regions residing ~115 and 200 bp upstream of the transcription start site. We found that the major fetal globin gene repressors BCL11A and ZBTB7A (also known as LRF) directly bound to the sites at -115 and -200 bp, respectively. Furthermore, introduction of naturally occurring HPFH-associated mutations into erythroid cells by CRISPR-Cas9 disrupted repressor binding and raised γ-globin gene expression. These findings clarify how these HPFH-associated mutations operate and demonstrate that BCL11A and ZBTB7A are major direct repressors of the fetal globin gene.
β-血红蛋白病，如镰状细胞病（SCD）和β-地中海贫血，是由于成人 HBB（β-珠蛋白）基因突变引起的。重新激活发育沉默的胎儿 HBG1 和 HBG2（γ-珠蛋白）基因是治疗 SCD 和 β-地中海贫血的治疗目标。遗传性胎儿血红蛋白持续存在（HPFH）的某些形式是一种罕见的良性病症，个体在整个成年期表达 γ-珠蛋白基因，其原因是 γ-珠蛋白基因启动子区域的点突变位于转录起始位点上游约 115 和 200bp。我们发现主要的胎儿珠蛋白基因抑制剂 BCL11A 和 ZBTB7A（也称为 LRF）分别直接结合到-115 和-200bp 的位点。此外，通过 CRISPR-Cas9 将天然存在的 HPFH 相关突变引入红细胞会破坏抑制剂结合并提高 γ-珠蛋白基因的表达。这些发现阐明了这些 HPFH 相关突变的作用机制，并表明 BCL11A 和 ZBTB7A 是胎儿珠蛋白基因的主要直接抑制剂。
