RRC ID 77232
Author Topfer SK, Feng R, Huang P, Ly LC, Martyn GE, Blobel GA, Weiss MJ, Quinlan KGR, Crossley M.
Title Disrupting the adult globin promoter alleviates promoter competition and reactivates fetal globin gene expression.
Journal Blood
Abstract The benign condition hereditary persistence of fetal hemoglobin (HPFH) is known to ameliorate symptoms of co-inherited β-hemoglobinopathies, such as sickle cell disease and β-thalassemia. The condition is sometimes associated with point mutations in the fetal globin promoters that disrupt the binding of the repressors BCL11A or ZBTB7A/LRF, which have been extensively studied. HPFH is also associated with a range of deletions within the β-globin locus that all reside downstream of the fetal HBG2 gene. These deletional forms of HPFH are poorly understood and are the focus of this study. Numerous different mechanisms have been proposed to explain how downstream deletions can boost the expression of the fetal globin genes, including the deletion of silencer elements, of genes encoding noncoding RNA, and bringing downstream enhancer elements into proximity with the fetal globin gene promoters. Here we systematically analyze the deletions associated with both HPFH and a related condition known as δβ-thalassemia and propose a unifying mechanism. In all cases where fetal globin is upregulated, the proximal adult β-globin (HBB) promoter is deleted. We use clustered regularly interspaced short palindromic repeats-mediated gene editing to delete or disrupt elements within the promoter and find that virtually all mutations that reduce ΗΒΒ promoter activity result in elevated fetal globin expression. These results fit with previous models where the fetal and adult globin genes compete for the distal locus control region and suggest that targeting the ΗΒΒ promoter might be explored to elevate fetal globin and reduce sickle globin expression as a treatment of β-hemoglobinopathies.
Volume 139(14)
Pages 2107-2118
Published 2022-4-7
DOI 10.1182/blood.2021014205
PII S0006-4971(22)00139-2
PMID 35090172
PMC PMC8990374
MeSH Carrier Proteins / genetics Cell Line, Tumor DNA-Binding Proteins / genetics Fetal Hemoglobin / genetics Fetal Hemoglobin / metabolism Gene Expression Globins* / metabolism Humans Transcription Factors / genetics beta-Globins / genetics beta-Globins / metabolism beta-Thalassemia* / genetics beta-Thalassemia* / therapy
IF 17.794
Human and Animal Cells HUDEP-2(RCB4557)