title: The Trans-Spliced Long Noncoding RNA tsRMST Impedes Human Embryonic Stem Cell Differentiation Through WNT5A-Mediated Inhibition of the Epithelial-to-Mesenchymal Transition.
abstract: The trans-spliced noncoding RNA RMST (tsRMST) is an emerging regulatory lncRNA in the human pluripotency circuit. Previously, we found that tsRMST represses lineage-specific transcription factors through the PRC2 complex and NANOG in human pluripotent stem cells (hESCs). Here, we demonstrate that tsRMST also modulates noncanonical Wnt signaling to suppress the epithelial-to-mesenchymal transition (EMT) and in vitro differentiation of embryonic stem cells (ESCs). Our results demonstrate that disruption of tsRMST expression in hESCs results in the upregulation of WNT5A, EMT, and lineage-specific genes/markers. Furthermore, we found that the PKC inhibitors Go6983 and Go6976 inhibited the effects of WNT5A, indicating that WNT5A promotes the EMT and in vitro differentiation although conventional and novel PKC activation in hESCs. Finally, we showed that either antiserum neutralization of WNT5A or Go6983 treatment in tsRMST knockdown cells decreased the expression of mesenchymal and lineage-specific markers. Together, these findings indicate that tsRMST regulates Wnt and EMT signaling pathways in hESCs by repressing WNT5A, which is a potential EMT inducer for promoting in vitro differentiation of hESCs through PKC activation. Our findings provide further insights into the role of trans-spliced RNA and WNT5A in hESC differentiation, in which EMT plays an important role. Stem Cells 2016;34:2052-2062.
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Yu
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005786:Gene Expression Regulation; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D020040:Trans-Splicing / Q000235:genetics*; D014157:Transcription Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; C430461:SUZ12 protein, human; D014157:Transcription Factors; C085389:WNT5A protein, human; C435831:WNT5B protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C000625304:long non-coding RNA tsRMST, human; D063151:Polycomb Repressive Complex 2; D011493:Protein Kinase C
keywords: EMT; Pluripotency; Trans-spliced RNA; WNT5A