CD34+ hematopoietic stem-progenitor cell microRNA expression and function: A circuit diagram of differentiation control

Abstract

MicroRNAs (miRNAs) are a recently identified class of epigenetic elements consisting of small noncoding RNAs that bind to the 3 untranslated region of mRNAs and down-regulate their translation to protein. miRNAs play critical roles in many different cellular processes including metabolism, apoptosis, differentiation, and development. We found 33 miRNAs expressed in CD34؉ hematopoietic stem-progenitor cells (HSPCs) from normal human bone marrow and mobilized human peripheral blood stem cell harvests. We then combined these data with human HSPC mRNA expression data and with miRNA-mRNA target predictions, into a previously undescribed miRNA:mRNA interaction database called the Transcriptome Interaction Database. The in silico predictions from the Transcriptome Interaction Database pointed to miRNA control of hematopoietic differentiation through translational control of mRNAs critical to hematopoiesis. From these predictions, we formulated a model for miRNA control of stages of hematopoiesis in which many of the genes specifying hematopoietic differentiation are expressed by HSPCs, but are held in check by miRNAs until differentiation occurs. We validated miRNA control of several of these target mRNAs by demonstrating that their translation in fact is decreased by miRNAs. Finally, we chose miRNA-155 for functional characterization in hematopoiesis, because we predicted that it would control both myelopoiesis and erythropoiesis. As predicted, miRNA-155 transduction greatly reduced both myeloid and erythroid colony formation of normal human HSPCs. expression analysis ͉ hematopoiesis ͉ stem cell

Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis

“…Most importantly, miR-155 is involved in the process of oncogenesis (40). Under physiologic conditions, this miRNA has been shown to be involved in the differentiation of hematopoietic progenitor cells (17,40). Recent experiments with miR-155-knockdown mice described an important role for miR-155 in the normal function of the immune system.…”

“…Initially, miR-155 was characterized as an oncogenic miRNA and was shown to be dysregulated in a large number of human neoplastic diseases (16). Subsequently, miR-155 was shown to be involved in the modulation of hematopoiesis, and very recently, its importance in the normal function of the immune system has been demonstrated (17)(18)(19).…”

Monitoring microRNAs Using a Molecular Beacon in CD133+/CD338+Human Lung Adenocarcinoma-initiating A549 Cells

“…Moreover, miRNAs have been implicated in the control of self-renewal in stem cells (Hatfield and Ruohola-Baker, 2008). Georgantas et al found that miRNA-155 played a role in normal human myelopoiesis, lung differentiation, and erythropoieis, and a recent study has shown that a high level of hsamiR-155 is associated with a poor outcome in lung cancer (Georgantas et al, 2007;Wang et al, 2009b). Thus, the detection of related miRNAs in TICs is an important strategy for the early diagnosis of lung cancer.…”

Gene expression changes in normal haematopoietic cells

“…[35][36][37][38] The expression of many miRNAs (e.g., miR-181) fluxuate during hematopoiesis, consistent with recent studies demonstrating a critical role for these transcripts in normal differentiation programs. 35,36,39 Other ncRNAs may serve as a physical linkers between RNA-binding proteins (e.g., translocation in liposarcoma, TLS) and DNA promoter sequences. In this model, the ncRNAs cause an allosteric change within the RNA-binding protein, which, in turn, promotes the association of other transcriptional proteins and represses promoter activity.…”