The switch from fetal to adult hemoglobin.
Open accessAbstract
The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and β-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and β-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.
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Infants with TDT or SCD are usually asymptomatic while fetal hemoglobin is high and become symptomatic in the first year as fetal hemoglobin falls.
“Neonates and infants with TDT or SCD are typically asymptomatic while their fetal hemoglobin levels remain high and become symptomatic during the first year of life when the synthesis of fetal hemoglobin declines 23,24 (Fig. 1A).”
From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [23]
In “THE FETAL-TO-ADULT GLOBIN SWITCH” (page not provided), the paper says infants with β-thalassemia begin to show symptoms as HbF declines in the months after birth. It also links elevated HbF to an asymptomatic period in SCD, but says symptoms appear after infancy rather than during the first year; it discusses β-thalassemia generally, not TDT specifically. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe 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 [23]
The section on early molecular studies reports that variants within BCL11A are associated with HbF levels and that experimentally knocking down BCL11A induces γ-globin expression. It does not say those SNPs lie in an erythroid-specific enhancer or establish that the SNPs themselves lower BCL11A expression and thereby raise HbF. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThis developmental switch is tightly regulated by epigenetic modifications, including DNA methylation and histone modifications, as well as by long-range interactions mediated by the locus control region (LCR) upstream of the β-globin cluster.
“This developmental switch is tightly regulated by epigenetic modifications, including DNA methylation and histone modifications, as well as by long-range interactions mediated by the locus control region (LCR) upstream of the β-globin cluster [94,95].”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [95]
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Experimental — accuracy not yet measuredBCL11A 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 [23]
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References 104 · Cited by 333
- Authors
- Sankaran, V. G., & Orkin, S. H.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-12-03
- Volume
- 3
- Issue
- 1
- Pages
- a011643-a011643
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC3530042
- OpenAlex
- W2170845283
- Cited by
- 333
- References
- 104
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 37 · 2023: 31 · 2022: 27 · 2021: 31 · 2020: 36 · 2019: 23 · 2018: 14 · 2017: 15 · 2016: 18 · 2015: 17 · 2014: 18 · 2013: 11 · 2012: 2
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL032259, T32HL007574)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- fetal hemoglobin, fetal to adult hemoglobin switch, sickle cell disease, beta-thalassemia, BCL11A, MYB, KLF1
- MeSH terms
- Adult, Anemia, Sickle Cell, Carrier Proteins, DNA-Binding Proteins, Fetal Hemoglobin, Hemoglobin A, Humans, Nuclear Proteins, Repressor Proteins, Transcription Factors, Transcriptional Activation, RNA-Binding Proteins, beta-Thalassemia, Nucleocytoplasmic Transport Proteins, Kruppel-Like Transcription Factors, Molecular Targeted Therapy
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