MicroRNA expression in maturing megakaryocytes
ABSTRACT MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down-regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up-regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously.
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- "Recently, Opalinska et al (2010) examined global miRNA expression during the differentiation of murine haematopoietic progenitors into MKs. Their findings extended the repertoire of differentially regulated miRNAs during murine megakaryocytopoiesis and further illustrated the regulating effect of miRNA in megakaryocytopoiesis (Opalinska et al, 2010). "
ABSTRACT: Megakaryocytopoiesis is governed by a complex network of haematopoietic growth factors that regulate the different stages of the process, in which haematopoietic stem cells undergo megakaryocytic lineage commitment, proliferation, maturation, and functional activation to produce platelets. MicroRNAs (miRNA) are a class of about 22-nucleotide noncoding RNAs that have been highly conserved during evolution and play a significant role in haematopoiesis, including differentiation and lineage commitment of megakaryocyte. This review summarizes the miRNAs which have changed expression during megakaryocytopoiesis, and their positive and negative functions on megakaryocytic differentiation. In addition, the abnormal miRNA expression profiles in megakaryocytic disorders are reviewed.British Journal of Haematology 09/2011; 155(3):298-307. DOI:10.1111/j.1365-2141.2011.08859.x · 4.96 Impact Factor
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ABSTRACT: MicroRNAs are small RNA molecules that modulate protein expression by degrading mRNA or repressing translation. They have been shown to play important roles in hematopoiesis, including embryonic stem cell differentiation, erythropoiesis, granulocytopoiesis/monocytopoiesis, lymphopoiesis, and megakaryocytopoiesis. miR-150 and miR-155 play divergent roles in megakaryocytopoiesis, with the former promoting development of megakaryocytes at the expense of erythrocytes and the latter causing a reduction in megakaryocyte colony formation. Platelets also contain fully functional miRNA machinery, and certain miRNA levels in platelets have been found to coordinate with reactivity to specific agonists and to pathologic states. This review will cover the current state of knowledge of miRNAs in megakaryocytes and platelets and the exciting possibilities for future research.Blood 03/2011; 117(20):5289-96. DOI:10.1182/blood-2011-01-292011 · 10.43 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) regulate cell physiology by altering protein expression, but the biology of platelet miRNAs is largely unexplored. We tested whether platelet miRNA levels were associated with platelet reactivity by genome-wide profiling using platelet RNA from 19 healthy subjects. We found that human platelets express 284 miRNAs. Unsupervised hierarchical clustering of miRNA profiles resulted in 2 groups of subjects that appeared to cluster by platelet aggregation phenotypes. Seventy-four miRNAs were differentially expressed (DE) between subjects grouped according to platelet aggregation to epinephrine, a subset of which predicted the platelet reactivity response. Using whole genome mRNA expression data on these same subjects, we computationally generated a high-priority list of miRNA-mRNA pairs in which the DE platelet miRNAs had binding sites in 3'-untranslated regions of DE mRNAs, and the levels were negatively correlated. Three miRNA-mRNA pairs (miR-200b:PRKAR2B, miR-495:KLHL5, and miR-107:CLOCK) were selected from this list, and all 3 miRNAs knocked down protein expression from the target mRNA. Reduced activation from platelets lacking PRKAR2B supported these findings. In summary, (1) platelet miRNAs are able to repress expression of platelet proteins, (2) miRNA profiles are associated with and may predict platelet reactivity, and (3) bioinformatic approaches can successfully identify functional miRNAs in platelets.Blood 03/2011; 117(19):5189-97. DOI:10.1182/blood-2010-09-299719 · 10.43 Impact Factor