Transcriptomics

Dataset Information

9

Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts


ABSTRACT: Diamond Blackfan Anemia (DBA) is associated with developmental defects and profound anemia. Mutations in genes encoding a ribosomal protein of the small (e.g. Rps19) or large (e.g. Rpl11) ribosomal subunit are found in over half of these patients. The mutations cause ribosomal haploinsufficiency, which reduces overall translation efficiency of cellular mRNAs. We reduced expression of *Rps19* or *Rpl11* in mouse erythroblasts and investigated mRNA polyribosome association, which revealed deregulated translation initiation of specific transcripts. Among these were *Bag1*, encoding a Hsp70 co-chaperone, and *Csde1*, encoding an RNA binding protein, both expressed at increased levels in erythroblasts. Their translation initiation is cap-independent and starts from an internal ribosomal entry site (IRES), which appeared sensitive to knock down of Rps19 or Rpl11. Mouse embryos lacking Bag1 die at embryonic day E13.5 with reduced erythroid colony forming cells in the fetal liver, and low Bag1 expression impairs erythroid differentiation in vitro. Reduced expression of Csde1 impairs proliferation and differentiation of erythroid blasts. Protein but not mRNA expression of *BAG1* and *CSDE1* was reduced in erythroblasts cultured from DBA patients. Our data suggest that impaired IRES-mediated translation of mRNAs expressed at increased levels in erythroblasts contributes to the erythroid phenotype of DBA. 3 biological replicates of erythroblasts treated with different shRNA were used for polyribosomal sucrose gradients; RNA was extracted from gradients in 2 samples - mRNA associated with polyribosomes (poly) and the rest (sub).

ORGANISM(S): Mus musculus  

SUBMITTER: Hanna H Ijspeert   Ivo I Touw  Erdogan E Taskesen  Marieke M von Lindern  Erdogan Taskesen  Rastislav R Horos  Dagmar D Pospisilova  Andrzej A Nieradka  Radek R Cmejla 

PROVIDER: E-GEOD-22903 | ArrayExpress | 2011-11-14

SECONDARY ACCESSION(S): GSE22903PRJNA127953

REPOSITORIES: GEO, ArrayExpress

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Publications

Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts.

Horos Rastislav R   Ijspeert Hanna H   Pospisilova Dagmar D   Sendtner Regine R   Andrieu-Soler Charlotte C   Taskesen Erdogan E   Nieradka Andrzej A   Cmejla Radek R   Sendtner Michael M   Touw Ivo P IP   von Lindern Marieke M  

Blood 20111104 1


Diamond-Blackfan anemia (DBA) is associated with developmental defects and profound anemia. Mutations in genes encoding a ribosomal protein of the small (e.g., RPS19) or large (e.g., RPL11) ribosomal subunit are found in more than half of these patients. The mutations cause ribosomal haploinsufficiency, which reduces overall translation efficiency of cellular mRNAs. We reduced the expression of Rps19 or Rpl11 in mouse erythroblasts and investigated mRNA polyribosome association, which revealed d  ...[more]

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