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 Gehrke; Aviv Regev; Eric S Lander; Hanna T Gazda; Winston Y Lee; Vikram G Panse; Steven A Carr; Vijay G Sankaran

doi:10.1016/j.cell.2018.02.036

Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis

Cell. 2018 Mar 22;173(1):90-103.e19. doi: 10.1016/j.cell.2018.02.036. Epub 2018 Mar 15.

Authors

Rajiv K Khajuria¹, Mathias Munschauer², Jacob C Ulirsch³, Claudia Fiorini³, Leif S Ludwig³, Sean K McFarland³, Nour J Abdulhay³, Harrison Specht², Hasmik Keshishian², D R Mani², Marko Jovanovic², Steven R Ellis⁴, Charles P Fulco², Jesse M Engreitz², Sabina Schütz⁵, John Lian⁶, Karen W Gripp⁷, Olga K Weinberg⁸, Geraldine S Pinkus⁹, Lee Gehrke⁶, Aviv Regev², Eric S Lander², Hanna T Gazda¹⁰, Winston Y Lee⁹, Vikram G Panse⁵, Steven A Carr², Vijay G Sankaran¹¹

Affiliations

¹ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
⁵ Institute of Medical Microbiology, Department of Medicine, University of Zurich, 8006 Zurich, Switzerland.
⁶ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA.
⁷ Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE 19803, USA.
⁸ Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
⁹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: sankaran@broadinstitute.org.

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.

Keywords: Diamond-Blackfan anemia; GATA1; erythropoiesis; genetics; hematopoiesis; lineage commitment; ribosome; translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions
Anemia, Diamond-Blackfan / genetics
Anemia, Diamond-Blackfan / pathology*
Apoptosis Regulatory Proteins / antagonists & inhibitors
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Bone Marrow Cells / metabolism
Cells, Cultured
Female
GATA1 Transcription Factor / genetics
GATA1 Transcription Factor / metabolism
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism
Humans
Male
Mutation, Missense
RNA Interference
RNA, Small Interfering / metabolism
Ribosomal Proteins / antagonists & inhibitors
Ribosomal Proteins / genetics
Ribosomal Proteins / metabolism
Ribosomes / genetics
Ribosomes / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

5' Untranslated Regions
Apoptosis Regulatory Proteins
GATA1 Transcription Factor
GATA1 protein, human
RNA, Small Interfering
Ribosomal Proteins
TSR2 protein, human
Transcription Factors
ribosomal protein L5, human
ribosomal protein S19

Abstract

Publication types

MeSH terms

Substances

Grants and funding