Abstract
Long noncoding RNAs (lncRNAs) constitute a significant fraction of mammalian transcriptomes and they have emerged as intricate regulators of many biological processes. Their broad capacity to adopt diverse structures facilitates their involvement in the transcriptional, translational and signaling processes that are central to embryonic stem (ES) cell self-renewal and pluripotency. While lncRNAs have been implicated in ES cell maintenance, detailed analyses of those that show significant expression in ES cells is largely absent. Moreover, cooperative molecular relationships that facilitate lncRNA action are poorly understood. Cyrano is a developmentally important lncRNA, and in ES cells, it supports gene expression network maintenance, cell adhesion and cell survival. We have interrogated the interactome of Cyrano to identify protein partners and find that Cyrano is involved in multiple protein networks. We identify a developmentally important cell-signaling hub and find STAT3 as a candidate through which Cyrano can function to reinforce self-renewal of ES cells. Based on commonalities between ES cells and cancer cells, we postulate such functional interactions may support cell proliferation, cell identity and adhesion characteristics in rapidly proliferating cell types. The interactome data will therefore provide a resource for further investigations into interactions that regulate Cyrano or mediate its function.
Highlights
Methods used to interrogate Long noncoding RNAs (lncRNAs)-protein interactions are protein-centric, and are limited to known RNA-binding proteins (RBPs)[7,8,9]
We propose that the role of lncRNAs in pluripotent stem cell biology requires further study, the intermolecular interactions through which lncRNAs contribute to embryonic stem (ES) cell maintenance
We assessed Cyrano’s genomic characteristics relative to all lncRNAs and mRNAs and found that Cyrano is among the longest lncRNA transcripts (Fig. 1A,B) in mouse (Cyrano/1700020I14Rik; p-value: 0.0019) and human (OIP5-AS1; p-value: 0.003)
Summary
Methods used to interrogate lncRNA-protein interactions are protein-centric, and are limited to known RNA-binding proteins (RBPs)[7,8,9]. Embryonic stem cells are pluripotent derivatives of the inner cell mass of blastocyst-stage embryos[11,12,13] Based on their developmental plasticity and their capacity for unlimited self-renewal, they hold significant potential for use in regenerative medicine, and are important models for dissecting early developmental processes. While numerous lncRNAs are expressed in ES cells, only a limited number have been functionally implicated in pluripotent cell maintenance through broad screens and/or individual candidate studies[14,15,16,17]. These studies show lncRNAs act in transcriptional regulation and post-transcriptional regulatory roles to support self-renewal and pluripotency of ES cells. We expand the network of the developmentally important lncRNA Cyrano, which we have previously shown supports the characteristics of ES cell self-renewal, to include proteins with which it may function to support ES cell maintenance
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