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| Status |
Public on Jan 29, 2018 |
| Title |
Natural regulatory mutations elevate fetal globin via disruption of BCL11A or ZBTB7A binding |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
B-hemoglobinopathies such as Sickle Cell Disease (SCD) and b-thalassemia result from mutations in the adult b-globin gene. Reactivating the developmentally silenced fetal g-globin gene is a therapeutic goal for treating SCD and b-thalassemia1. Some forms of Hereditary Persistence of Fetal Hemoglobin (HPFH), a rare benign condition in which individuals express g‑globin throughout adulthood, are caused by point mutations in the g‑globin gene promoter at regions residing ~115 and 200 base pairs upstream of the transcription start site. Here we show that the major fetal globin repressors BCL11A and ZBTB7A/LRF directly bind to the -115 and ‑200 sites, respectively. Furthermore, introduction of naturally occurring HPFH mutations into erythroid cells by CRISPR/Cas9 disrupts repressor binding and raises g‑globin expression. These findings resolve the mystery surrounding how these HPFH mutations operate and demonstrate that BCL11A and ZBTB7A/LRF are major direct repressors of the fetal globin gene.
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| Overall design |
ChIP-seq experiments were performed in two different cell lines, HUDEP-2 and K562 against BCL11A and ZBTB7A. Input samples were used as control.
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| Contributor(s) |
Martyn GE, Wienert B, Yang L, Shah M, Norton LJ, Burdach J, Kurita R, Nakamura Y, Pearson RC, Funnell AP, Quinlan KG, Crossley M |
| Citation(s) |
29610478 |
| Submission date |
Sep 05, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Merlin Crossley |
| Organization name |
University of New South Wales
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| Department |
BABS
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| Street address |
UNSW
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| City |
Sydney |
| State/province |
NSW |
| ZIP/Postal code |
2052 |
| Country |
Australia |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA401837 |
| SRA |
SRP116907 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE103445_HUDEP2_BCL11A_optimal_idr_peaks.bed.gz |
170.8 Kb |
(ftp)(http) |
BED |
| GSE103445_K562_ZBTB7A_optimal_idr_peaks.bed.gz |
166.3 Kb |
(ftp)(http) |
BED |
| GSE103445_RAW.tar |
4.9 Gb |
(http)(custom) |
TAR (of BEDGRAPH, TXT) |
| GSE103445_hg38_modified_chr11.genome.gz |
4.7 Mb |
(ftp)(http) |
GENOME |
| GSE103445_hg38_modified_chr11_genome.fa.gz |
937.6 Mb |
(ftp)(http) |
FA |
| GSE103445_hg38refGene_modified_chr11.txt.gz |
4.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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