Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)90-103.e19
JournalCell
Volume173
Issue number1
DOIs
StatePublished - Mar 22 2018
Externally publishedYes

Keywords

  • Diamond-Blackfan anemia
  • erythropoiesis
  • GATA1
  • genetics
  • hematopoiesis
  • lineage commitment
  • ribosome
  • translation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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