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Series GSE194064 Query DataSets for GSE194064
Status Public on Jan 20, 2022
Title Disrupting the adult-globin promoter alleviates promoter competition and reactivates foetal-globin gene expression
Organism Homo sapiens
Experiment type Other
Summary The benign condition Hereditary Persistence of Foetal Haemoglobin (HPFH) is known to ameliorate symptoms when co-inherited with beta-haemoglobinopathies, such as sickle cell disease and beta-thalassaemia. The condition is sometimes associated with point mutations in the foetal 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 beta-globin locus that all reside downstream of the foetal 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 foetal globin genes, including the deletion of silencer elements, of genes encoding non-coding RNA, and bringing downstream enhancer elements into proximity with the foetal globin gene promoters. Here we systematically analyse the deletions associated with both HPFH and a related condition known as beta-thalassaemia and propose a unifying mechanism. In all cases where foetal globin is up-regulated, the proximal adult beta-globin (HBB) promoter is deleted. We use CRISPR gene editing to delete or disrupt elements within the promoter and find that virtually all mutations that reduce promoter activity, result in elevated foetal globin expression. These results fit with previous models where the foetal and adult globin genes compete for the distal Locus Control Region and suggest that targeting the promoter might be explored to elevate foetal globin and reduce sickle globin expression as a treatment for beta-haemoglobinopathies.
Overall design We performed Capture-C on WT control, HBB promoter deletion and TATA deletion clones. Two replicates were performed for each condition.
Contributor(s) Crossley M
Citation(s) 35090172
Submission date Jan 20, 2022
Last update date Jan 31, 2022
Contact name Peng Huang
Organization name Guangzhou Medical University
Department GMU-GIBH Joint School of Life Sciences
Lab Peng Huang
Street address Xinzao, Panyu District
City Guangzhou
State/province Guangdong
ZIP/Postal code 511436
Country China
Platforms (1)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (6)
GSM5827251 HUDEP2_WT_r1
GSM5827252 HUDEP2_WT_r2
GSM5827253 HUDEP2_dPromoter_r1
BioProject PRJNA798972

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GSE194064_RAW.tar 1.5 Mb (http)(custom) TAR (of BIGWIG)
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Raw data are available in SRA
Processed data provided as supplementary file

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