Regulated expression of microRNAs-126/126* inhibits erythropoiesis from human embryonic stem cells

Abstract

IntroductionThe hematopoietic system is hierarchically organized, with a rare population of hematopoietic stem cells giving rise to specific progenitor cells and ultimately to diverse mature blood cell types. Lineage-specific fate decisions are intricately controlled by sets of master transcription factors. 1 For example, erythroid versus myeloid lineage differentiation is based on transcriptional crossantagonism between GATA-1 and PU.1. 2 PU.1 and C/EBP␣ are required for the generation of both macrophages and neutrophils. 3 In addition to transcription factors that are pivotal for hematopoietic cell lineage specification, several developmentally conserved signaling pathways, including Notch, Wnt, Sonic hedgehog, and TGF-␤, have also been implicated in regulating lineage determination. 4 MicroRNAs (miRs) are a recently discovered class of small (20-22 nt) noncoding RNAs that control gene expression posttranscriptionally by regulating mRNA translation or stability. 5 The roles of miRs in regulating the hematopoietic system are still poorly understood, although a series of recent studies have provided some perspective on this important issue. 6 There are several miRs, including miR-142, miR-181a, and miR-223, that are prominently expressed in hematopoietic cells. 7,8 Ectopic expression of miR-181a in hematopoietic stem/progenitor cells promotes B-cell differentiation, whereas overexpression of miR-142 and miR-223 leads to an increase in the proportion of T-lineage cells. 7 Some studies have not only delineated a role for miRs in hematopoiesis but also uncovered their molecular mechanisms of action involving regulation of lineage determining transcription factors. For example, the combination of gain-of-function and loss-of-function strategies has defined the requirement of miR-150 in B-cell differentiation by targeting the transcription factor c-Myb. 9 During monocytopoiesis, down-regulation of miRs 17-5p-20a-106a relieves the suppression of AML1, thus facilitating monocytic differentiation and maturation. 10 In addition to the role of specific miRs, the general requirement of miRs in hematopoiesis has been demonstrated, as deletion of Dicer in the thymus results in aberrant T-cell development in the murine system. 11,12 There is expanding literature suggesting that miRs also play an important role in the pathology of hematologic malignancies as tumor suppressor genes or oncogenes. For example, both miR-15a and miR-16 are deleted or down-regulated in the majority of chronic lymphocytic leukemia cases, 13 whereas C57BL6 mice transplanted with murine hematopoietic progenitor cells overexpressing miR-155 developed a myeloproliferative disorder. 14 Given compelling evidence that miRs are essential in the hematopoietic system, we sought to elucidate the potential roles of miRs in early human hematopoietic development. Insights into hematopoietic development have largely relied on findings from gene knockout and transgenic mouse models as well as in other model organisms. Because of the inaccessibility of human embryos,...

MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation

“…by guest www.bloodjournal.org From leads to a decrease in erythroid colony formation; megakaryocyte potential was not assessed by this report. 42 However, expression of miR-126 decreases with megakaryocyte differentiation from adult CD34 ϩ cells. 43 Lastly, several groups have reported the aberrant expression of miR-126 in acute myeloid leukemia-initiating cells.…”

Expression of miR-126 and Crk in endometriosis: miR-126 may affect the progression of endometriosis by regulating Crk expression

“…Aberrant expression of miRNAs can lead to numerous diseases, including EMs. miR-126 is a miRNA involved in the regulation of cell growth, cell differentiation, apoptosis, cell motility, cell adhesion, cell invasion, and angiogenesis [8][9][10][11][12]. Crk is an oncogene that binds to many signaling molecules through the SH2/SH3 domain, such as phosphorylated tyrosine motifs and proline-rich motifs present in proteins.…”

Transcription factor networks in erythroid cell and megakaryocyte development

“…109 An additional microRNA, miR-126, inhibits red cell production from in vitro differentiation of human embryonic stem cells, although this report does directly test whether this effect is acting at the stage of erythromegakaryocytic fate decision. 110 …”