Long Noncoding RNA Moderates MicroRNA Activity to Maintain Self-Renewal in Embryonic Stem Cells

Abstract

SummaryOf the thousands of long noncoding RNAs expressed in embryonic stem cells (ESCs), few have known roles and fewer have been functionally implicated in the regulation of self-renewal and pluripotency, or the reprogramming of somatic cells to the pluripotent state. In ESCs, Cyrano is a stably expressed long intergenic noncoding RNA with no previously assigned role. We demonstrate that Cyrano contributes to ESC maintenance, as its depletion results in the loss of hallmarks of self-renewal. Delineation of Cyrano's network through transcriptomics revealed widespread effects on signaling pathways and gene expression networks that contribute to ESC maintenance. Cyrano shares unique sequence complementarity with the differentiation-associated microRNA, mir-7, and mir-7 overexpression reduces expression of a key self-renewal factor to a similar extent as Cyrano knockdown. This suggests that Cyrano functions to restrain the action of mir-7. Altogether, we provide a view into the multifaceted function of Cyrano in ESC maintenance.

Potential application of cell reprogramming techniques for cancer research

“…In addition to the reprogramming factors mentioned above, other reprogramming enhancers, including miRNAs and lncRNAs [194], have been emerging. These are also factors that are key to overcoming the obstacles to cancer cell reprogramming (Table 1).…”

LncRNAOIP5-AS1is overexpressed in undifferentiated oral tumors and integrated analysis identifies as a downstream effector of stemness-associated transcription factors

“…LncRNAs, with less or no protein coding potential, are shown to be involved in early embryonic development to cancer metastasis [12,23]. OIP5-AS1, a long intergenic ncRNA transcribed in antisense from the OIP5 gene, located at chromosome 15q15.1, was first discovered as cyrano in zebrafish and reported to function as a major regulator of neurogenesis during development and in the maintenance of self-renewal in mouse morula stage modulating the nanog expression by sponging mmu-miR-7 [16,17]. The function of this lncRNA in human development/cancer is not clear and there are only a couple of studies highlighting its role in human cancers.…”

“…In the mouse embryo, overexpression of Oip5-as1 (1700020I14Rik) was shown to maintain stemness by regulating the steady state level of NANOG through sponging of mmu-miR-7a [16][17][18].…”

“…LncRNAs function by acting as signals, decoys, guides, and scaffolds and as a repressor or activator of gene transcription and translation. cryano (linc-oip5) is a long intergenic ncRNA, first identified in Zebrafish has been reported to be overexpressed in morula stage of the mouse embryo and maintains stem cell selfrenewal in embryo through modulation of NANOG by sponging Nanog targeting miR-7a [16,17]. The human counterpart of cryano is OIP5-AS1, which is transcribed from OIP5 gene in antisense orientation and its function in human cancer is yet to be explored.…”

Interactions between short and long noncoding RNAs

“…There appear to be numerous parallels between the TDMD caused by Nrep and Cyrano. Both RNAs are quite abundant and predominantly cytoplasmic [96][97][98] and both contain unusually complementary sitesthe highly conserved region in Cyrano contains an 8mer pairing to the 5 0 of miR-7 and another 13 bases pairing to its 3 0 , thus pairing with all bases of miR-7 except 9 and 10 ( Fig. 3) [95,97].…”