Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis
Open accessAbstract
Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.
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Functional follow-up showed that the more common ribosomal gene mutations impair the translation of GATA1 mRNA and thus result in impaired erythropoiesis.
“Inspired by this discovery and through functional follow up, it was shown that the more common ribosomal gene mutations impair the translation of GATA1 mRNA and thus result in impaired erythropoiesis (Khajuria et al., 2018; Ludwig et al., 2014).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Khajuria et al., 2018
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- Authors
- Khajuria, R. K., Munschauer, M., Ulirsch, J. C., Fiorini, C., Ludwig, L. S., McFarland, S. K., Abdulhay, N. J., Specht, H., Keshishian, H., Mani, D. R., Jovanovic, M., Ellis, S. R., Fulco, C. P., Engreitz, J. M., Schütz, S., Lian, J., Gripp, K. W., Weinberg, O. K., Pinkus, G. S., Gehrke, L., Regev, A., Lander, E. S., Gazda, H. T., Lee, W. Y., Panse, V. G., Carr, S. A., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- University of Louisville (US)
- University of Zurich (CH)
- Harvard University (US)
- Alfred I. duPont Hospital for Children (US)
- Boston Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Sankaran, Vijay G.
- ORCID
- Khajuria, Rajiv K.
- Munschauer, Mathias
- Ulirsch, Jacob C.
- Fiorini, Claudia
- Ludwig, Leif S.
- Abdulhay, Nour J.
- Specht, Harrison
- Keshishian, Hasmik
- Mani, D.R.
- Ellis, Steven R.
- Fulco, Charles P.
- Engreitz, Jesse M.
- Lian, John
- Gripp, Karen W.
- Weinberg, Olga K.
- Gehrke, Lee
- Regev, Aviv
- Lander, Eric S.
- Gazda, Hanna T.
- Panse, Vikram G.
- Carr, Steven A.
- Sankaran, Vijay G.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 173
- Issue
- 1
- Pages
- 90-103.e19
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5866246
- OpenAlex
- W2793800931
- Cited by
- 416
- References
- 60
- Citations by year
- 2026: 40 · 2025: 35 · 2024: 47 · 2023: 48 · 2022: 52 · 2021: 51 · 2020: 71 · 2019: 46 · 2018: 26
- FWCI
- 17.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Boehringer Ingelheim
- NIH (T32 HL007574, R01 DK103794, R33 HL120791)
- Swiss National Science Foundation
- Novartis Foundation
- Olga Mayenfisch Stiftung
- European Research Council (EURIBIO260676)
- DBA Foundation
- March of Dimes
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- translational regulation, lineage commitment, hematopoiesis, hematopoietic stem and progenitor cells, Diamond-Blackfan anemia, ribosomal proteins, erythroid differentiation, ribosome composition, blood cell differentiation
- MeSH terms
- Bone Marrow Cells, Cells, Cultured, Female, Hematopoietic Stem Cells, Humans, Male, Ribosomal Proteins, Ribosomes, Transcription Factors, 5' Untranslated Regions, Mutation, Missense, Anemia, Diamond-Blackfan, RNA Interference, RNA, Small Interfering, GATA1 Transcription Factor, Apoptosis Regulatory Proteins
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