Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis
Name
nihms944917.pdf
Description
Accepted version
Size
2.57 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Khajuria, Rajiv K.
Munschauer, Mathias
Ulirsch, Jacob C.
Fiorini, Claudia
Ludwig, Leif S.
McFarland, Sean K.
Abdulhay, Nour J.
Specht, Harrison
Keshishian, Hasmik
Mani, Denkanikota R
Date Issued
March 2018
Journal
Cell
Publisher
Elsevier BV
Citation
Khajuria, Rajiv K, et al. "Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis." Cell 173, 1 (March 2018): 90–103 © 2018 Elsevier Inc.
Version
Author's final manuscript
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. A global reduction in ribosome levels in Diamond-Blackfan anemia profoundly alters translation of a select subset of transcripts, thereby impeding erythroid lineage commitment. Keyword: hematopoiesis; lineage commitment; GATA1; genetics; ribosome; translation; Diamond-Blackman anemia; erythropoiesis
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1103/10.1016/j.cell.2018.02.036
