Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation
Open accessAbstract
Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and β-thalassemia 1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development 2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.
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BCL11A expression is controlled by transcriptional and/or translational mechanisms.
“BCL11A expression is controlled by transcriptional and/or translational mechanisms.[22][23][24]”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [22]
Prior to the first genome-wide association studies into variation that impacts fetal hemoglobin levels, the regulators of fetal hemoglobin were poorly understood.
“For instance, prior to the first genome-wide association studies (GWAS) into variation that impacts fetal hemoglobin (HbF) levels - an important ameliorating factor for sickle cell disease and β-thalassemia - the regulators of HbF were poorly understood (Basak et al., 2020).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Basak et al., 2020
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References 53 · Cited by 105
- Authors
- Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., Rice, C. M., An, X., Christou, H. A., Mohandas, N., Carr, S. A., Chen, J.-J., Orkin, S. H., Lander, E. S., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- New York Blood Center (US)
- Rockefeller University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Basak, Anindita
- Sankaran, Vijay G.
- ORCID
- Basak, Anindita
- Munschauer, Mathias
- Lareau, Caleb A.
- Montbleau, Kara E.
- Ulirsch, Jacob C.
- Hartigan, Christina R.
- Schenone, Monica
- Lian, John
- Wang, Yaomei
- Huang, Yumin
- Wu, Xianfang
- Gehrke, Lee
- Rice, Charles M.
- An, Xiuli
- Christou, Helen A.
- Mohandas, Narla
- Carr, Steven A.
- Chen, Jane-Jane
- Orkin, Stuart H.
- Lander, Eric S.
- Sankaran, Vijay G.
- Venue
- Nature Genetics
- Published
- 2020-01-20
- Volume
- 52
- Issue
- 2
- Pages
- 138-145
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC7031047
- OpenAlex
- W2998852785
- Cited by
- 105
- References
- 53
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 17 · 2023: 20 · 2022: 11 · 2021: 23 · 2020: 12
- FWCI
- 8.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (U01 HL117720)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- hemoglobin switching, fetal hemoglobin, BCL11A, LIN28B, mRNA translation regulation, ribosome-associated mRNA, RNA-binding proteins, erythroid development, sickle cell disease, beta-thalassemia, let-7 microRNA, protein synthesis inhibition
- MeSH terms
- Adult, Animals, Binding Sites, Cells, Cultured, Erythropoiesis, Gene Expression Regulation, Hemoglobins, Humans, Infant, Newborn, Repressor Proteins, Ribosomes, RNA, Messenger, RNA, Ribosomal, 18S, Protein Biosynthesis, RNA-Binding Proteins, MicroRNAs, Erythroid Cells
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