An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level
Open accessAbstract
BCL11A Variants: Recent chromatin mapping data have suggested that trait-associated variants often mark regulatory DNA. However, there has been little rigorous experimental investigation of regulatory variation. Bauer et al. (p. 253 ; see the Perspective by Hardison and Blobel ) performed an in-depth study of the BCL11A fetal hemoglobin-associated locus. The trait-associated variants revealed a chromatin signature that enhanced erythroid development. The enhancer was required for erythroid expression of BCL11A and thus for globin gene expression.
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The BCL11A erythroid-specific enhancer consists of 3 DNase hypersensitive sites 162, 158, and 155 kb from the transcription initiation site.
“This enhancer consists of 3 DNase hypersensitive sites 162, 158, and 155 kb from the transcription initiation site.19”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [19]
The passage on DNase I hypersensitivity reports three erythroid sites in BCL11A intron 2, supporting the claim's site count. But it places them at +62, +58 and +55 kb from the transcription start site, not 162, 158 and 155 kb. (LLM, conf=0.90)
Experimental — accuracy not yet measuredGenomewide association studies found SNPs associated with higher fetal hemoglobin in adults.
“Genomewide association studies have identified single-nucleotide polymorphisms (SNPs) associated with increased expression of fetal hemoglobin in adults.26”
From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [26]
Functional variants of BCL11A are marked by single nucleotide polymorphisms in intron 2 that tag an erythroid-specific enhancer.
“Functional variants of BCL11A are marked by single nucleotide polymorphisms (SNPs) in intron 2 that tag an erythroid-specific enhancer.19”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [19]
The sentinel SNP marking the BCL11A QTL is rs1427407.
“The sentinel SNP marking this QTL is rs1427407.”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [19]
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- Authors
- Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., Sabo, P. J., Vierstra, J., Voit, R. A., Yuan, G.-C., Porteus, M. H., Stamatoyannopoulos, J. A., Lettre, G., & Orkin, S. H.
- Affiliations
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Montreal Heart Institute (CA)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- University of Washington (US)
- Stanford University (US)
- Corresponding author
- Orkin, Stuart H.
- ORCID
- Venue
- Science
- Published
- 2013-10-11
- Volume
- 342
- Issue
- 6155
- Pages
- 253-257
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4018826
- OpenAlex
- W2008989169
- Semantic Scholar
- 2845316815fa241ea105cf77d04cc6906bf4c64b
- Cited by
- 653
- References
- 54
- Citations by year
- 2026: 42 · 2025: 50 · 2024: 64 · 2023: 42 · 2022: 47 · 2021: 48 · 2020: 45 · 2019: 38 · 2018: 49 · 2017: 48 · 2016: 80 · 2015: 59 · 2014: 37 · 2013: 4
- FWCI
- 29.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Canadian Institutes of Health Research (123382)
- National Heart, Lung, and Blood Institute (P01HL032262, R01HL032259)
- National Human Genome Research Institute (U54HG007010, U54HG004594, R01HG005085)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK049216, K08DK093705)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- BCL11A, fetal hemoglobin, common genetic variants, transcription factor binding, fine mapping, erythroid cells, B cells, β-hemoglobinopathies, genome editing
- MeSH terms
- Animals, Carrier Proteins, Cells, Cultured, Chromatin, Chromosome Mapping, Enhancer Elements, Genetic, Fetal Hemoglobin, Gene Expression Regulation, Genetic Engineering, Hemoglobinopathies, Humans, Nuclear Proteins, Repressor Proteins, Transcription Factors, Genetic Variation, Gene Targeting, Erythroid Cells, Cell Line, Tumor, Chromatin Immunoprecipitation, Mice, Precursor Cells, B-Lymphoid, Genome-Wide Association Study
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