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

Of the thousands of long non-coding RNAs expressed in embryonic stem (ES) cells, few have known roles and fewer have been functionally implicated in the regulation of self-renewal and pluripotency or reprogramming somatic cells to the pluripotent state. In ES cells, Cyrano is a stably expressed long intergenic non-coding RNA with no previously assigned role. We demonstrate that Cyrano contributes to ES cell maintenance, as its depletion results in 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 ES cell 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 ES cell maintenance. Overall design: RNA-seq on mouse R1 embryonic stem (ES) cells with two biological replicates transfected with an shRNA knockdown of Cyrano and two biological replicates transfected with a non-targeting control vector.

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Smith KN, Starmer J, Miller SC, Sethupathy P, Magnuson T