An Ultraconserved Element Containing lncRNA Preserves Transcriptional Dynamics and Maintains ESC Self-Renewal

Summary

Ultraconserved elements (UCEs) show the peculiar feature to retain extended perfect sequence identity among human, mouse, and rat genomes. Most of them are transcribed and represent a new family of long non-coding RNAs (lncRNAs), the transcribed UCEs (T-UCEs). Despite their involvement in human cancer, the physiological role of T-UCEs is still unknown. Here, we identify a lncRNA containing the uc.170+, named T-UCstem1, and provide in vitro and in vivo evidence that it plays essential roles in embryonic stem cells (ESCs) by modulating cytoplasmic miRNA levels and preserving transcriptional dynamics. Specifically, while T-UCstem1::miR-9 cytoplasmic interplay regulates ESC proliferation by reducing miR-9 levels, nuclear T-UCstem1 maintains ESC self-renewal and transcriptional identity by stabilizing polycomb repressive complex 2 on bivalent domains. Altogether, our findings provide unprecedented evidence that T-UCEs regulate physiological cellular functions and point to an essential role of T-UCstem1 in preserving ESC identity.

Graphical Abstract

Highlights

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  The transcribed ultraconserved element T-UCstem1 exerts a dual function in ESCs

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  T-UCstem1 controls ESC proliferation by regulating the miR-9/Lin28b molecular axis

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  T-UCstem1 maintains ESC self-renewal

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  T-UCstem1 preserves ESC transcriptional identity by stabilizing PRC2

Abstract

In this article Fico, Minchiotti, and colleagues identify an ultraconserved element containing long non-coding RNA, named T-UCstem1, in embryonic stem cells (ESCs) and provide evidence that it regulates cell-cycle progression by modulating cytoplasmic miR-9 levels and preserves ESC identity and self-renewal by stabilizing polycomb repressive complex 2 (PRC2) on bivalent domains.