Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond-Blackfan Anemia.
Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to "ribosomal stress" with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Anna
A
Aspesi
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Elisa
E
Pavesi
Department of Sciences and Technological Innovation, University of Eastern Piedmont, Alessandria, Italy.
Elisa
E
Robotti
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Rossella
R
Crescitelli
Department of Chemistry, University of Milan, Italy.
Ilenia
I
Boria
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Federica
F
Avondo
U1009, AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Université Paris VII-Denis Diderot, Sorbonne Paris Cité, F-75475 Paris, France.
Hélène
H
Moniz
U1009, AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Université Paris VII-Denis Diderot, Sorbonne Paris Cité, F-75475 Paris, France.
Lydie
L
Da Costa
New York Blood Center, NY, USA.
Narla
N
Mohandas
International School for Advanced Studies (SISSA/ISAS), Trieste, Italy.
Paola
P
Roncaglia
Department of Pediatric Sciences, University of Torino, Torino, Italy.
Ugo
U
Ramenghi
Department of Biotechnologies and Biosciences, Milano-Bicocca University, Italy.
Antonella
A
Ronchi
International School for Advanced Studies (SISSA/ISAS), Trieste, Italy.
Stefano
S
Gustincich
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Simone
S
Merlin
Department of Sciences and Technological Innovation, University of Eastern Piedmont, Alessandria, Italy.
Emilio
E
Marengo
University of Louisville, KY, USA.
Steven R
SR
Ellis
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Antonia
A
Follenzi
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Claudio
C
Santoro
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy. Electronic address: irma.dianzani@med.unipmn.it.
Irma
I
Dianzani
D017398:Alternative Splicing; D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D023061:Gene Order; D006801:Humans; D058977:Molecular Sequence Annotation; D009154:Mutation; D010641:Phenotype; D015203:Reproducibility of Results; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C040343:ribosomal protein S19
Bone marrow failure; Diamond Blackfan Anemia; Ribosomal protein; Ribosomopathy