Endogenous miRNA Sponge lincRNA-RoR Regulates Oct4, Nanog, and Sox2 in Human Embryonic Stem Cell Self-Renewal

Abstract

The embryonic stem cell (ESC) transcriptional and epigenetic networks are controlled by a multilayer regulatory circuitry, including core transcription factors (TFs), posttranscriptional modifier microRNAs (miRNAs), and some other regulators. However, the role of large intergenic noncoding RNAs (lincRNAs) in this regulatory circuitry and their underlying mechanism remains undefined. Here, we demonstrate that a lincRNA, linc-RoR, may function as a key competing endogenous RNA to link the network of miRNAs and core TFs, e.g., Oct4, Sox2, and Nanog. We show that linc-RoR shares miRNA-response elements with these core TFs and that linc-RoR prevents these core TFs from miRNA-mediated suppression in self-renewing human ESC. We suggest that linc-RoR forms a feedback loop with core TFs and miRNAs to regulate ESC maintenance and differentiation. These results may provide insights into the functional interactions of the components of genetic networks during development and may lead to new therapies for many diseases.

Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells

“…Both computational and experimental evidence support the extensive targeting of lncRNAs by miRNAs (Paraskevopoulou et al 2013). While a small number of lncRNAs are currently known to function as ceRNAs (Cesana et al 2011;Fan et al 2013;Wang et al 2013;Tan et al 2014), the full extent of lncRNAs possessing miRNA-dependent regulatory roles remains to be determined (Ulitsky and Bartel 2013).…”

“…Cell-fate decisions, such as those involving linc-RoR or linc-MD1, often involve switch-like responses in the expression levels of key regulatory genes that result in coordinated changes in transcription profiles driven by one or more key transcription factors. Several miRNAs have been found to contribute to the regulation of such switches (Mukherji et al 2011), and lncRNAs have often been implicated in the regulation of the circuitry underlying cell-fate decisions (Jia et al 2010;Cesana et al 2011;Guttman et al 2011;Sun et al 2013;Wang et al 2013). These results suggest that relatively lowly abundant, yet specifically expressed, lncRNAs might function efficiently as ceRNAs regulating the transition between pluripotent and differentiated cell states.…”

“…The miRNA-mediated crosstalk among transcripts can involve coding as well as noncoding transcripts, including intergenic long noncoding RNAs (lncRNAs) (Franco-Zorrilla et al 2007;Cesana et al 2011;Wang et al 2013). Thousands of lncRNAs have been annotated in eukaryotic genomes (Derrien et al 2012;Ulitsky and Bartel 2013), many of which are preferentially located in the cytoplasm (van Heesch et al 2014), where they can engage in miRNA-mediated interactions with other transcripts.…”

“…Nevertheless, some established ceRNAs neither share an unusually high number of predicted MREs with their mRNA targets nor are especially abundant (Cesana et al 2011;Wang et al 2013), which suggests that other factors, such as miRNA-target affinity or miRNA turnover, might explain their efficient crosstalk. These ceRNAs are also no different from most other lncRNAs (Cabili et al 2011;Derrien et al 2012) with respect to their highly restricted spatial and temporal expression patterns.…”

“…These ceRNAs are also no different from most other lncRNAs (Cabili et al 2011;Derrien et al 2012) with respect to their highly restricted spatial and temporal expression patterns. For example, linc-MD1 is a muscle-specific ceRNA that regulates transcript abundance of two key myogenic transcription factors, Maml1 and Mef2c, which are required for activating muscle-specific gene expression (Cesana et al 2011); in addition, linc-RoR competes for miR-145 binding with key self-renewal transcription factor transcripts, namely Nanog, Pou5f1, and Sox2, and is expressed during induced pluripotent stem cell (iPSC) reprogramming and in undifferentiated embryonic stem cells (ESCs) (Loewer et al 2010;Wang et al 2013). The narrow expression profile of these ceRNAs might specify the cells or tissues in which their activity exerts the greatest effect.…”