Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding

• Published in: Nature genetics Vol. 50; no. 4; pp. 498 - 503
• Main Authors: Martyn, Gabriella E., Wienert, Beeke, Yang, Lu, Shah, Manan, Norton, Laura J., Burdach, Jon, Kurita, Ryo, Nakamura, Yukio, Pearson, Richard C. M., Funnell, Alister P. W., Quinlan, Kate G. R., Crossley, Merlin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2018; Nature Publishing Group
• Subjects: 38/109; 38/39; 42; 45/15; 45/70; 45/77; 631/208/200; 631/337; 82; 82/16; 96; Agriculture; Animal Genetics and Genomics; Binding; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cancer Research; CRISPR; Deoxyribonucleic acid; Disruption; DNA; Erythroid cells; Fetuses; Gene expression; Gene Function; Gene mutation; Genes; Genomes; Globin genes; Glycosylated hemoglobin; Health aspects; Hemoglobin; Hemoglobinopathies; Hemoglobins; Human Genetics; Letter; Mutation; Proteins; Repressors; Sickle cell anemia; Sickle cell disease; Thalassemia; Transcription; Transcription (Genetics); Transcription factors; Transcriptional coactivators
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-018-0085-0

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 1 . 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. The fetal globin gene repressors BCL11A and ZBTB7A directly bind γ-globin gene promoter regions. Repressor binding is disrupted by naturally occurring point mutations located upstream of the transcriptional start site that are associated with hereditary persistence of fetal hemoglobin.