Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos IMicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455: 1124-1128

Stem Cell and Developmental Biology, Genome Institute of Singapore, Agency for Science Technology and Research, #08-01, Genome, 60 Biopolis Street, Singapore 138672, Singapore.
Nature (Impact Factor: 41.46). 10/2008; 455(7216):1124-8. DOI: 10.1038/nature07299
Source: PubMed


MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3' untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3' untranslated region.

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    • "One of the important factors involved in self-renewal and maintenance of HSCs multipotency of CD34 stem cells is Sall4 transcription factor (TF) (Aguila et al., 2011). Sall4 is zinc-finger TF belong to spalt-1ike protein family, located on chromosome 20 and expressed in undifferentiated stem cells like normally embryonic stem cells (ESCs) and CD34 + HSCs (Tay et al., 2008). Sall4 binds to regulatory regions of ESCs master regulators such as Nanog and Oct-4 and regulates their expression (Wu et al., 2006; Zhang et al., 2006; Tan et al., 2013). "
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    ABSTRACT: Hematopoietic Stem Cells (HSCs) are cells that have the ability to self-renewal and differentiate into all of hematopoietic lineages. The lack of donors and unavailable efficient protocols for ex vivo expansion of HSCs, are obstacles in successful cell therapies. MicroRNAs (also refer as miRNAs or miRs) have significant roles in hematopoiesis; they can effect on HSCs expansion, maintaining undifferentiated state, self-renewal and differentiation. Recently attentions have been given to these small regulatory molecules to utilize them in order to expand HSCs. Using bioinformatics analysis we identified Sall4 as putative target of miR-15b and miR-219-5p. Relative expression levels of miRNAs and Sall4 were evaluated by qRT-PCR. Here we show 247-fold and 4.2fold increasing Sall4 expression level compared to control group in CD34+ cells nucleofected by anti-miR-15b and anti-miR-219-5p, respectively. These data showed that anti-miR-15b can promote clonogenic capacity of HSCs and also we found that miR-15b alone was able to increase the number of CD34+HSCs in vitro by more than 2 fold by targeting Sall4. Moreover, level of CD34 marker in HSCs nucleofected by anti-miR-15b increased more than 50%. Our analysis showed no statistically difference in mRNA level of Sall4 after nucleofection of anti-miR-219-5p. Sall4 is a factor capable of enhancing HSC expansion significantly. We demonstrated that inhibition of miR-15b can enhance ex vivo expansion of UCB-derived HSCs and also expression of Sall4 allowed expansion and preserve self- renewal of CD34+ HSCs. © 2015, Leibniz Research Centre for Working Environment and Human Factors. All rights reserved.
    EXCLI Journal 05/2015; 14:601-610. DOI:10.17179/excli2014-687 · 0.86 Impact Factor
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    • "MicroRNAs are a class of 17–24 nt small, noncoding RNAs, which mediate post-transcriptional gene silencing by binding to the 3-untranslated region (UTR) or open reading frame (ORF) region of target mRNAs [5]. The involvement of miRNAs in many biological activities has been well documented, including cell proliferation, cell differentiation, cell migration, disease initiation, and disease progression [6] [7] [8] [9] [10]. "
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    ABSTRACT: Exosomes are 40-100 nm nano-sized vesicles that are released from many cell types into the extracellular space. Such vesicles are widely distributed in various body fluids. Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells and subsequently modulate recipient cells. This suggests an active sorting mechanism of exosomal miRNAs, since the miRNA profiles of exosomes may differ from those of the parental cells. Exosomal miRNAs play an important role in disease progression, and can stimulate angiogenesis and facilitate metastasis in cancers. In this review, we will introduce the origin and the trafficking of exosomes between cells, display current research on the sorting mechanism of exosomal miRNAs, and briefly describe how exosomes and their miRNAs function in recipient cells. Finally, we will discuss the potential applications of these miRNA-containing vesicles in clinical settings. Copyright © 2015. Production and hosting by Elsevier Ltd.
    Genomics Proteomics & Bioinformatics 02/2015; 21(1). DOI:10.1016/j.gpb.2015.02.001
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    • "This phenomenon may be somewhat exaggerated, however, as many miRNA target prediction programs consider only 3 0 -UTRs in predictions of miRNA binding (Lewis et al. 2005; Wang and El Naqa 2008; Maragkakis et al. 2009). Indeed, miRNA target sites located within coding sequences have been documented in animals (Forman et al. 2008; Tay et al. 2008), including humans (Forman et al. 2008), and have recently been suggested to be a common occurrence in cnidarians (Moran et al. 2014). There is some evidence suggesting that miRNA binding in coding regions may require higher sequence complementarity between the miRNA and its target, and proceed via RISC-mediated cleavage (Duursma et al. 2008). "
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    ABSTRACT: MicroRNAs (miRNAs) are involved in post-transcriptional regulation of gene expression l regulation of gene expressionvelopment to reory genese likely false positives. too approximate.rgence times that I cited init. Since several miRNAs are known to affect the stability or translation of developmental regulatory genes, the origin of novel miRNAs may have contributed to the evolution of developmental processes and morphology. Lepidoptera (butterflies and moths) is a species-rich clade with a well-established phylogeny and abundant genomic resources, thereby representing an ideal system in which to study miRNA evolution. We sequenced small RNA libraries from developmental stages of two divergent lepidopterans, Cameraria ohridella (Horse chestnut Leafminer) and Pararge aegeria (Speckled Wood butterfly), discovering 90 and 81 conserved miRNAs respectively, and many species-specific miRNA sequences. Mapping miRNAs onto the lepidopteran phylogeny reveals rapid miRNA turnover and an episode of miRNA fixation early in lepidopteran evolution, implying that miRNA acquisition accompanied the early radiation of the Lepidoptera. One lepidopteran-specific miRNA gene, miR-2768, is located within an intron of the homeobox gene invected, involved in insect segmental and wing patterning. We identified cubitus interruptus (ci) as a likely direct target of miR-2768, and validated this suppression using a luciferase assay system. We propose a model by which miR-2768 modulates expression of ci in the segmentation pathway and in patterning of lepidopteran wing primordia. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
    Molecular Biology and Evolution 01/2015; 32(5). DOI:10.1093/molbev/msv004 · 9.11 Impact Factor
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