ATAXIN2 is crucial for megakaryocyte protein homeostasis and proper platelet functionality
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63297 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA267222
REPOSITORIES: GEO
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Project description:Megakaryocytes accumulate mRNA during their maturation, which is required for the correct spatio-temporal production of cytoskeletal proteins, membranes and platelet-specific granules, and for the subsequent shedding of thousands of platelets per cell. Gene expression profiling identified the RNA binding protein ATAXIN2 (ATXN2) as a putative novel regulator of megakaryopoiesis. ATXN2 expression is high in CD34+/CD41+ megakaryoblasts and sharply decreases upon maturation to megakaryocytes. ATXN2 associates with DDX6 suggesting that it may mediate repression of mRNA translation during early megakaryopoiesis. Comparative transcriptome and proteome analysis on megakaryoid cells (MEG-01) with differential ATXN2 expression identified ATXN2 dependent gene expression of mRNA and protein involved in processes linked to coagulation. Mice deficient for Atxn2 did not display differences in bleeding times, but expression of key surface receptors on platelets, such as ITGB3 (carries the CD61 antigen) and CD31 (PECAM1), were deregulated and platelet aggregation upon specific triggers was reduced.
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Project description:Megakaryocytes accumulate mRNA during their maturation, which is required for the correct spatio-temporal production of cytoskeletal proteins, membranes and platelet-specific granules, and for the subsequent shedding of thousands of platelets per cell. Gene expression profiling identified the RNA binding protein ATAXIN2 (ATXN2) as a putative novel regulator of megakaryopoiesis. ATXN2 expression is high in CD34+/CD41+ megakaryoblasts and sharply decreases upon maturation to megakaryocytes. ATXN2 associates with DDX6 suggesting that it may mediate repression of mRNA translation during early megakaryopoiesis. Comparative transcriptome and proteome analysis on megakaryoid cells (MEG-01) with differential ATXN2 expression identified ATXN2 dependent gene expression of mRNA and protein involved in processes linked to coagulation. Mice deficient for Atxn2 did not display differences in bleeding times, but expression of key surface receptors on platelets, such as ITGB3 (carries the CD61 antigen) and CD31 (PECAM1), were deregulated and platelet aggregation was reduced upon specific triggers.
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Project description:All mRNAs are bound in vivo by proteins to form mRNA–protein complexes (mRNPs), but changes in the composition of mRNPs during post-transcriptional regulation remain largely unexplored. Here, we have analyzed, on a transcriptome-wide scale, how microRNA-mediated repression modulates the associations of core components (eIF4E, eIF4G, and PABP) and of the decay factor DDX6 in human cells. Despite the transient nature of repressed intermediates, we detected significant changes in mRNP composition, marked by dissociation of eIF4G and PABP, and by recruitment of DDX6. Furthermore, although poly(A)-tail length has been considered critical in post-transcriptional regulation, differences in steady-state tail length explained little of the variation in either PABP association or mRNP organization more generally. Instead, relative occupancy of core components correlated best with gene expression. Together, these results indicate that posttranscriptional regulatory factors influence the associations of PABP and other core factors, and do so without substantially affecting steady-state tail length.
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