@article{5e28b2d94f72400e810da9fe0d66b4e1,
title = "Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis",
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.",
keywords = "Diamond-Blackfan anemia, GATA1, erythropoiesis, genetics, hematopoiesis, lineage commitment, ribosome, translation",
author = "Khajuria, {Rajiv K.} and Mathias Munschauer and Ulirsch, {Jacob C.} and Claudia Fiorini and Ludwig, {Leif S.} and McFarland, {Sean K.} and Abdulhay, {Nour J.} and Harrison Specht and Hasmik Keshishian and Mani, {D. R.} and Marko Jovanovic and Ellis, {Steven R.} and Fulco, {Charles P.} and Engreitz, {Jesse M.} and Sabina Sch{\"u}tz and John Lian and Gripp, {Karen W.} and Weinberg, {Olga K.} and Pinkus, {Geraldine S.} and Lee Gehrke and Aviv Regev and Lander, {Eric S.} and Gazda, {Hanna T.} and Lee, {Winston Y.} and Panse, {Vikram G.} and Carr, {Steven A.} and Sankaran, {Vijay G.}",
note = "Funding Information: We thank D. Nathan, S. Orkin, L. Zon, K. Patel, S. Eichhorn, Z. Ji, J. Clohessy, A. Bolze, and Sankaran laboratory members for valuable discussions. We are grateful to T. DiCesare for assistance with illustrations. R.K.K received partial support from a Boehringer Ingelheim MD Fellowship. S.K.M. received support from the NIH ( T32 HL007574 ). A.R. is an investigator of the Howard Hughes Medical Institute. V.G.P. received support from the Swiss National Science Foundation , Novartis Foundation , Olga Mayenfisch Stiftung , and the European Research Council ( EURIBIO260676 ). V.G.S. is a Principal Faculty member of the Harvard Stem Cell Institute. This work was supported by the NIH ( R01 DK103794 and R33 HL120791 ), as well as a grant from the DBA Foundation and a March of Dimes Basil O{\textquoteright}Connor Scholar Award (to V.G.S.). Funding Information: We thank D. Nathan, S. Orkin, L. Zon, K. Patel, S. Eichhorn, Z. Ji, J. Clohessy, A. Bolze, and Sankaran laboratory members for valuable discussions. We are grateful to T. DiCesare for assistance with illustrations. R.K.K received partial support from a Boehringer Ingelheim MD Fellowship. S.K.M. received support from the NIH (T32 HL007574). A.R. is an investigator of the Howard Hughes Medical Institute. V.G.P. received support from the Swiss National Science Foundation, Novartis Foundation, Olga Mayenfisch Stiftung, and the European Research Council (EURIBIO260676). V.G.S. is a Principal Faculty member of the Harvard Stem Cell Institute. This work was supported by the NIH (R01 DK103794 and R33 HL120791), as well as a grant from the DBA Foundation and a March of Dimes Basil O'Connor Scholar Award (to V.G.S.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = mar,
day = "22",
doi = "10.1016/j.cell.2018.02.036",
language = "English (US)",
volume = "173",
pages = "90--103.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}