Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms

Posttranscriptional and translational controls mediated by microRNAs (miRNA) regulate diverse biologic processes. We dissected regulatory effects of miRNAs relevant to megakaryocytopoiesis and platelet biology by analyzing expression patterns in 79 subjects with thrombocytosis and controls, and inte...

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Bibliographic Details
Published in:Blood 2012-10, Vol.120 (17), p.3575-3585
Main Authors: Xu, Xiao, Gnatenko, Dmitri V., Ju, Jingfang, Hitchcock, Ian S., Martin, Dwight W., Zhu, Wei, Bahou, Wadie F.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Binding Sites
Biological and medical sciences
Blood Platelets - metabolism
Blood Platelets - pathology
Cell Differentiation
Cell Lineage - genetics
Cells, Cultured
Female
Gene Expression Profiling
Gene Expression Regulation, Developmental
Genes, Reporter
Hematologic and hematopoietic diseases
Humans
Lentivirus
Luciferases
Male
Mass Spectrometry
Medical sciences
Megakaryocytes - metabolism
Megakaryocytes - pathology
Microfilament Proteins
MicroRNAs - genetics
MicroRNAs - metabolism
Oligonucleotide Array Sequence Analysis
Platelets and Thrombopoiesis
Protein Binding
Proteomics
rho GTP-Binding Proteins
Thrombocythemia, Essential - genetics
Thrombocythemia, Essential - metabolism
Thrombocythemia, Essential - pathology
Thrombopoiesis - genetics
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Summary:Posttranscriptional and translational controls mediated by microRNAs (miRNA) regulate diverse biologic processes. We dissected regulatory effects of miRNAs relevant to megakaryocytopoiesis and platelet biology by analyzing expression patterns in 79 subjects with thrombocytosis and controls, and integrated data with transcriptomic and proteomic platforms. We validated a unique 21-miRNA genetic fingerprint associated with thrombocytosis, and demonstrated that a 3-member subset defines essential thrombocythemia (ET). The genetic signature includes functional guide and passenger strands of the previously uncharacterized miR 490 (5p and 3p), which displayed restricted, low-level expression in megakaryocytes/platelets (compared with leukocytes), and aberrant expression during thrombocytosis, most profound in ET. Overexpression of miR 490 in a bilineage differentiation model of megakaryocyte/erythroid progenitor formation was insufficient for hematopoietic colony differentiation and/or lineage specification. Integration of transcriptomic and mass spectrometric datasets with functional reporter assays identified dishevelled associated activator of morphogenesis 1 (DAAM1) as a miR 490 5p protein target demonstrating decreased expression in ET platelets, putatively by translational control (and not by mRNA target degradation). Our data define a dysregulated miRNA fingerprint in thrombocytosis and support a developmentally restricted function of miR 490 (and its putative DAAM1 target) to conditions associated with exaggerated megakaryocytopoiesis and/or proplatelet formation.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-02-411264