From microRNAs to targets: Pathway discovery in cell fate transitions

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Department of Urology, University of California San Francisco, San Francisco, CA, USA.
Current opinion in genetics & development (Impact Factor: 8.57). 05/2011; 21(4):498-503. DOI: 10.1016/j.gde.2011.04.011
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) are 22 nt non-coding RNAs that regulate expression of downstream targets by messenger RNA (mRNA) destabilization and translational inhibition. A large number of eukaryotic mRNAs are targeted by miRNAs, with many individual mRNAs being targeted by multiple miRNAs. Further, a single miRNA can target hundreds of mRNAs, making these small RNAs powerful regulators of cell fate decisions. Such regulation by miRNAs has been observed in the maintenance of the embryonic stem cell (ESC) cell cycle and during ESC differentiation. MiRNAs can also promote the dedifferentiation of somatic cells to induced pluripotent stem cells. During this process they target multiple downstream genes, which represent important nodes of key cellular processes. Here, we review these findings and discuss how miRNAs may be used as tools to discover novel pathways that are involved in cell fate transitions using dedifferentiation of somatic cells to induced pluripotent stem cells as a case study.

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Available from: Robert Blelloch, Apr 23, 2015
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    • "Abbreviations used AGO, Argonaute sub-family of Argonaute proteins; Armi, Armitage; Aub, Aubergine; HP1, heterochromatin protein 1; LINE, long interspersed nuclear element; LTR, long terminal repeat elements; miRNAs, microRNAs; piRNAs, PIWI-interacting RNAs; PIWI, Piwi sub-family of Argonaute proteins; SINE, short interspersed nuclear element; siRNAs, smallinterfering RNAs; UTR, untranslated region; Vret, Vreteno; Zuc, Zucchini yeast and plants, thereby silencing gene transcription (Martienssen et al., 2008). The profound impact of small RNA pathways on gene regulation is obvious from the significant roles they play in a variety of biological processes including stem cell self-renewal and differentiation (Gangaraju and Lin, 2009; Subramanyam and Blelloch, 2011), various aspects of animal development (Stefani and Slack, 2008), germline development (Saxe and Lin, 2011), and human diseases including cancer (Esteller, 2011). It is increasingly clear that small RNA pathways exert significant control over the expression of large numbers of genes, and therefore can exert significant influence over gene networks. "
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    ABSTRACT: Small RNAs impact several cellular processes through gene regulation. Argonaute proteins bind small RNAs to form effector complexes that control transcriptional and post-transcriptional gene expression. PIWI proteins belong to the Argonaute protein family, and bind PIWI-interacting RNAs (piRNAs). They are highly abundant in the germline, but are also expressed in some somatic tissues. The PIWI/piRNA pathway has a role in transposon repression in Drosophila, which occurs both by epigenetic regulation and post-transcriptional degradation of transposon mRNAs. These functions are conserved, but clear differences in the extent and mechanism of transposon repression exist between species. Mutations in piwi genes lead to the upregulation of transposon mRNAs. It is hypothesized that this increased transposon mobilization leads to genomic instability and thus sterility, although no causal link has been established between transposon upregulation and genome instability. An alternative scenario could be that piwi mutations directly affect genomic instability, and thus lead to increased transposon expression. We propose that the PIWI/piRNA pathway controls genome stability in several ways: suppression of transposons, direct regulation of chromatin architecture, and regulation of genes that control important biological processes related to genome stability. The PIWI/piRNA pathway also regulates at least some, if not many, protein-coding genes, which further lends support to the idea that piwi genes may have broader functions beyond transposon repression. An intriguing possibility is that the PIWI/piRNA pathway is using transposon sequences to coordinate the expression of large groups of genes to regulate cellular function. Mol. Reprod. Dev. © 2013 Wiley Periodicals, Inc.
    Molecular Reproduction and Development 08/2013; 80(8). DOI:10.1002/mrd.22195 · 2.68 Impact Factor
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    • "(legend continued on next page) iPSC-inhibitory factor Prrx1 (Yang et al., 2011) is predicted to be targeted by miR-294. Unexpectedly, miR-302a, whose forced expression was also shown to enhance iPSC generation in the context of the Yamanaka factors (Subramanyam and Blelloch, 2011), exhibited transient activation specifically in Oct4-GFP+ cells at day 12 but remained otherwise unchanged (Figures S3G and S3H). Mir-302a is normally expressed in mouse epiblast stem cells (Huo and Zambidis, 2012) but barely detectable in mouse ESCs, suggesting that iPSC induction might entail a transient passage through an epiblast-like state before reaching naive pluripotency. "
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    ABSTRACT: Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we examined defined intermediate cell populations poised to becoming iPSCs by genome-wide analyses. We show that induced pluripotency elicits two transcriptional waves, which are driven by c-Myc/Klf4 (first wave) and Oct4/Sox2/Klf4 (second wave). Cells that become refractory to reprogramming activate the first but fail to initiate the second transcriptional wave and can be rescued by elevated expression of all four factors. The establishment of bivalent domains occurs gradually after the first wave, whereas changes in DNA methylation take place after the second wave when cells acquire stable pluripotency. This integrative analysis allowed us to identify genes that act as roadblocks during reprogramming and surface markers that further enrich for cells prone to forming iPSCs. Collectively, our data offer new mechanistic insights into the nature and sequence of molecular events inherent to cellular reprogramming.
    Cell 12/2012; 151(7):1617-32. DOI:10.1016/j.cell.2012.11.039 · 33.12 Impact Factor
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    • "Eberhardt et al. (2008), demonstrated for the first time that miRNA, in particular miR-140, affects cranial NC cells dispersion and modulates palatogenesis. After this pioneer work, several groups have demonstrated that miRNA are central regulators of NC development (Amaral and Mattick, 2008; Eberhart et al., 2008; Cordes and Srivastava, 2009; Xin et al., 2009; Ivey and Srivastava, 2010; Subramanyam and Blelloch, 2011). The conditional loss of the Drosha cofactor Dgcr8, which codes for a double stranded RNA-binding protein that is central for miRNA biogenesis, displayed a wide spectrum of malformations in cardiac NC cells, including persistent truncus arteriosus (PTA) and ventricular septal defect (VSD). "
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    ABSTRACT: The neural crest (NC) is a multipotent, migratory cell population that arises from the dorsal neural fold of vertebrate embryos. NC cells migrate extensively and differentiate into a variety of tissues, including melanocytes, bone, and cartilage of the craniofacial skeleton, peripheral and enteric neurons, glia, and smooth muscle and endocrine cells. For several years, the gene regulatory network that orchestrates NC cells development has been extensively studied. However, we have recently begun to understand that epigenetic and posttranscriptional regulation, such as miRNAs, plays important roles in NC development. In this review, we focused on some of the most recent findings on chromatin-dependent mechanisms and miRNAs regulation during vertebrate NC cells development. Developmental Dynamics, 2012. © 2012 Wiley Periodicals, Inc.
    Developmental Dynamics 12/2012; 241(12). DOI:10.1002/dvdy.23868 · 2.67 Impact Factor
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