Hemoglobin switching’s surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin.
Open accessAbstract
The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level. Studies of BCL11A exemplify how contextual gene regulation may often be the substrate for trait-associated common genetic variation. These discoveries have suggested novel rational approaches for the β-hemoglobin disorders including therapeutic genome editing.
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BCL11A acts as a repressor of γ-globin and fetal hemoglobin in erythroid cells.
“BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells.”
From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [1]
The fetal hemoglobin-associated SNPs lie in an erythroid-specific enhancer, lower BCL11A expression, and raise fetal hemoglobin.
“the SNPs that are associated with fetal hemoglobin are in an erythroid-specific enhancer, downregulate BCL11A expression, and increase the expression of fetal hemoglobin.1,23”
From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [1]
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References 75 · Cited by 143
- Authors
- Bauer, D. E., & Orkin, S. H.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Bauer, Daniel E
- Orkin, Stuart H
- Venue
- Current Opinion in Genetics & Development
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 33
- Pages
- 62-70
- ISSN
- 0959-437X (ISSN-L)
- PMC
- PMC4705561
- OpenAlex
- W2185201235
- Cited by
- 143
- References
- 75
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 19 · 2023: 18 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 11 · 2016: 19 · 2015: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Genetics & Development (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (DK093705, HL32259, HL032262, DK49216, HL117720)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- BCL11A, fetal hemoglobin, hemoglobin switching, transcriptional repression, zinc finger transcription factor, sickle cell disease, beta-thalassemia, beta-globin gene regulation, gamma-globin, genome-wide association study, common genetic variants
- MeSH terms
- Anemia, Sickle Cell, Carrier Proteins, Fetal Hemoglobin, Gene Expression Regulation, Humans, Nuclear Proteins, Repressor Proteins, beta-Thalassemia, Genome-Wide Association Study, beta-Globins
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