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

Autor: Martyn GE; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Wienert B; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Yang L; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Shah M; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Norton LJ; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Burdach J; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Kurita R; Research and Development Department, Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan., Nakamura Y; Cell Engineering Division, RIKEN BioResource Center, Ibaraki, Japan., Pearson RCM; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Funnell APW; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Quinlan KGR; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia., Crossley M; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, New South Wales, Australia. m.crossley@unsw.edu.au.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2018 Apr; Vol. 50 (4), pp. 498-503. Date of Electronic Publication: 2018 Apr 02.
DOI: 10.1038/s41588-018-0085-0
Abstrakt: 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.
Databáze: MEDLINE
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