Cited by 423RNA and protein synthesis mechanismsHematopoietic Stem Cell TransplantationBlood disorders and treatments

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Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis

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Khajuria, Rajiv K., Munschauer, Mathias, Ulirsch, Jacob C., Fiorini, Claudia, Ludwig, Leif S., McFarland, Sean K., Abdulhay, Nour J., Specht, Harrison, Keshishian, Hasmik, Mani, D.R., Jovanovic, Marko, Ellis, Steven R., Fulco, Charles P., Engreitz, Jesse M., Schütz, Sabina, Lian, John, Gripp, Karen W., Weinberg, Olga K., Pinkus, Geraldine S., Gehrke, Lee, Regev, Aviv, Lander, Eric S., Gazda, Hanna T., Lee, Winston Y., Panse, Vikram G., Carr, Steven A., Sankaran, Vijay G.·2018·Cell

DOI 10.1016/j.cell.2018.02.036PMC PMC5866246

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Abstract

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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Additional file 20 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 15 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 14 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 19 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 16 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 18 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 11 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 7 of A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion
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Additional file 9 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 1 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 7 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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Additional file 8 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
Wu, J., Xiao, Y., Sun, J., Sun, H., Chen, H., Zhu, Y., Fu, H., Yu, C., Weigao, E., Lai, S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13011084
Additional file 2 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
Wu, J., Xiao, Y., Sun, J., Sun, H., Chen, H., Zhu, Y., Fu, H., Yu, C., Weigao, E., Lai, S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13011066
Additional file 1 of A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion
Witte, F., Ruiz‐Orera, J., Mattioli, C. C., Blachut, S., Adami, E., Schulz, J. F., Schneider-Lunitz, V., Hummel, O., Patone, G., Mücke, M. B., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14870585
Additional file 4 of A single-cell survey of cellular hierarchy in acute myeloid leukemia
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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)
DOI: 10.1016/j.cell.2018.02.036
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
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
Health Sciences › Medicine › Hematology › 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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Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis

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