Table 1.
LncRNA Transcripts Differentially Expressed in ESCs and iPSCs with Their Roles in Pluripotency
| LncRNA | Role in pluripotent cells | Molecular mechanisms |
|---|---|---|
| Gomafu | This nervous system-expressed lncRNA shows dynamic regulation during development of neural stem cells and also in mESCs. Harbors the Oct4 binding site at the promoter. Moreover, it appears to control Oct4 expression in a regulatory feedback loop. | Post-transcriptional (Gomafu can bind the splicing factor 1 [SF1] protein through its UACUAAC repeat sequences that results in the post-transcriptional regulation of splicing efficiency. The molecular mechanisms involving Oct4 expression control in mESCs remain elusive though.) |
| Mira | This lncRNA is expressed from the spacer DNA region (SDR) separating Hoxa6 and Hoxa7, which is transcriptionally silent in ESCs, but activated by retinoic acid treatment on mESCs, recruits the epigenetic activator MLL1 to the Mira gene locus triggers transcription of Hoxa6 and Hoxa7. These genes in turn trigger the expression of a number of genes resulting in germ layer specification and exit from pluripotent state. | Epigenetic (Mira plays a part in the epigenetic regulation of Hoxa6 and Hoxa7 by mediating a local rearrangement in chromatin structure to bring the Mira, Hox66, and Hoxa7 loci into a complex providing a mechanism for MLL1 to act on HoxA6/A7 after recruitment to the Mira locus.) |
| HOTAIRM1 | This mESC-expressed lncRNA from the HOXA locus was found to interact with a number of chromatin-binding proteins/complexes in mESCs, including PRC1, PRC2, and CBX1, to exert a cis-regulatory effect on the genes from the HOXA cluster. | Epigenetic (HOTAIRM1 interacts with a number of chromatin-binding proteins/complexes in mESCs, including PRC1, PRC2, and CBX1, to regulate the genes from the HOXA cluster) |
| Xist | In female undifferentiated mES and iPS cells, Xist is not expressed, and both X-chromosomes are active. Xist repress paternal X-chromosome in female ESCs to facilitate exit from the pluripotent state. Xist lncRNA is expressed from only the inactive X-chromosome and coats the entire chromosome in cis to epigenetically silence the gene expression from that chromosome. The epigenetic silencing of one X involves recruitment of polycomb group to confer silencing epigenetic mark H3K27Me3 on histone. | Epigenetic (Xist plays a vital role in the epigenetic silencing of the inactive X chromosome by binding to PRC2 via RepA and recruiting it on the Xi resulting in the deposition of the repressive chromatin mark H3K27me3 on the Xi.) |
| Tsix | Among many regulators of Xist within the X-inactivation center in pluripotent female ESCs, perhaps the most well known is lncRNA Tsix, which transcribes from both alleles. It mediates repression of Xist by physically associating with DNA methyltransferase Dnmt3a at the Xist promoter, leading to DNA methylation and silencing of Xist only on the active X-chromosome. lincRNA Tsix and its activator lncRNA Xite are identified to be direct targets of Oct4 in mESCs. | Epigenetic (Tsix epigenetically silences Xist expression by inhibiting RepA recruitment of polycomb complexes to maintain the active X-chromosome in females.) |
| Xite | lncRNA Xite is one of the functional lncRNAs in the X-inactivation center and is found to be the activator of lncRNA Tsix expression. It is identified to be direct targets of Oct4 in mESCs. A second pluripotency transcription factor Sox2 also binds Xite. | Not known yet. |
| Jpx | This lncRNA in the X inactivation center (Xic) is upregulated during both male and female ESC differentiation. It is Involved in the regulation of X-chromosome inactivation in mammals via activation of the Xist RNA, possibly by interfering with Tsix expression. | Not known yet. |
| NEAT1 | In mESCs, Neat1 has been reported to interact with a number of chromatin-binding protein/complexes in mESCs, including PRC1, PRC2,JARID1B, ESET, and SUV39H1, with the general pattern being interaction with repressors of gene expression [39]. In human, NEAT1 is not expressed in ESCs and it has been found to regulate mRNA cytoplasmic export for mRNAs containing inverted repeated Alu by facilitating nuclear paraspeckle formation in differentiated cells. |
Epigenetic/Post-transcriptional (Neat1 has been reported to interact with a number of chromatin-binding protein/complexes in mESCs, including PRC1, PRC2, JARID1B, ESET, and SUV39H1; while in human, NEAT1 is not expressed in ESCs, and it has been found to regulate the mRNA cytoplasmic export for mRNAs containing inverted repeated Alu by facilitating nuclear paraspeckle formation in differentiated cells. |
| Rian |
Rian transcripts bind to the PRC2-chromatin-modifying complex in mESCs. Rian was also found to interact with a number of other chromatin-binding proteins/complexes in mESCs, including PRC1, JARID1B, JARID1C, and CBX3, with the general pattern being interaction with repressors of gene expression [39]. This lncRNA is located in the imprinted Dlk1-Dio3 gene cluster on chromosome 12qF1, which is normally expressed in the ESCs, were found to be aberrantly silenced in most of the iPSC clones in a comparison of genetically identical mESCs and mouse iPSCs. These iPSCs failed to support development of entirely iPSC-derived animals. |
Epigenetic (Rian transcripts bind to the PRC2 chromatin-modifying complex in mESCs.) |
| Sox2ot | This mESC expressed transcript is downregulated upon induction of embryoid body (EB) differentiation like Sox2, but, unlike Sox2, is upregulated during EB late differentiation. | Not known yet |
| lncRNA-ES1-3 | These three hESC-specific lncRNAs are likely to be regulated by pluripotency-associated transcription factors OCT4 and/or NANOG, as these lncRNAs showed decreased expression after RNAi knockdown of NANOG and/or OCT4 in hESCs. | Not known yet |
| lincRNA-RoR (enriched in iPSCs) | This lincRNA is found enriched in both ESCs and iPSCs compared to the fibroblast and CD34 cells, but with increased level in iPSCs compared to ESCs, which suggest its potential role in reprogramming. This possibility was further supported by the fact that knockdown of this lincRNA resulted in reduced colony formation in iPSCs without affecting the cell number, whereas overexpression increased the number of iPSC colonies formed. It has a binding site for pluripotency-associated transcription factors Oct4, Sox2, and Nanog. Functions to promote reprogramming of differentiated cells to iPSCs. |
Not known yet |
| lincRNA-SFMBT2 (enriched in iPSCs) | This lincRNA is found enriched in both ESCs and iPSCs compared to the fibroblast and CD34 cells, but with an increased level in iPSCs compared to ESCs, which suggest its potential role in reprogramming. However, its knockdown did not affect generation of iPSC cells, suggesting that it is not essential to this process.It harbors the binding site for pluripotency transcription factors Oct4, Sox2, and Nanog. Knockdown of Oct4 or differentiation of stem cells caused downregulation of lincRNA-SFMBT2 expression, suggesting that expression is controlled by these transcription factors. | Not known yet |
| lincRNA-VLDLR (enriched in iPSCs) | This lincRNA is found enriched in both ESCs and iPSCs compared to the fibroblast and CD34 cells, but with increased level in iPSCs compared to ESCs, which suggest its potential role in reprogramming. However, its knockdown did not affect generation of iPSC cells, suggesting that it is not essential to this process. It harbors the binding site for pluripotency transcription factors Oct4, Sox2, and Nanog. Knockdown of Oct4 or differentiation of stem cells caused downregulation of lincRNA-SFMBT2 expression, suggesting that expression is controlled by these transcription factors. It is reported to have a synthetic correlate expressed in mESCs. |
Not known yet |
| MEG3 (expressed in ESCs, but aberrantly silenced in iPSCs) | Meg3 is important for proper growth and development and is a putative tumor suppressor. This lncRNA is located in the imprinted Dlk1-Dio3 gene cluster on chromosome 12qF1, which is normally expressed in the ESCs, were found to be aberrantly silenced in most of the iPSC clones in a comparison of genetically identical mESCs and mouse iPSCs. These iPSCs failed to support the development of entirely iPSC-derived animals. | Not known yet |
| MEG9 (expressed in ESCs, but aberrantly silenced in iPSCs) |
Meg9/Mirg is expressed in embryonic and extraembryonic tissue. Transcripts from the Meg9 locus bind to the PRC2 chromatin modification complex in mESCs. This lncRNA is located in the imprinted Dlk1-Dio3 gene cluster on chromosome 12qF1, which is normally expressed in the ESCs, were found to be aberrantly silenced in most of the iPSC clones in a comparison of genetically identical mESCs and mouse iPSCs. These iPSCs failed to support the development of entirely iPSC-derived animals. |
Epigenetic (Meg9 binds to the PRC2 chromatin modification complex in mESCs). |
ESCs, embryonic stem cells; iPSCs, induced pluripotent stem cells; mESC, mouse ESC.