Gas5 is an essential lncRNA regulator for self-renewal and pluripotency of mouse embryonic stem cells and induced pluripotent stem cells

Tu, Jiajie; Tian, Geng; Cheung, Hoi‐Hung; Wei, Wei; Lee, Tin‐Lap

doi:10.1186/s13287-018-0813-5

Cited by 48 publications

(40 citation statements)

References 29 publications

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“…Similarly, nutritional deprivation as well as chemotherapy also induced expression of Sox2, Oct4 and Nanog expression 25 . Literature shows that GAS5 is regulated by Sox2 34, 38 . To see if in CD133+ pancreatic cancer cells Sox2 regulated GAS5 mediated growth arrest, we next silenced Sox2 (with siRNA) and studied the expression of GAS5 in CD133 Hi cells.…”

Section: Resultsmentioning

confidence: 99%

“…It also mediates cell proliferation by regulating CDK6 activity 17 . Studies have also shown that GAS5 forms a positive feedback network with a number of genes involved in self-renewal like Sox2/Oct4, making this long non-coding RNA (LncRNA) a critical player in induction and maintenance of the “stemness” state in a tumor 34 . GAS5 is further involved in regulation of human embryonic stem cell self-renewal by maintaining NODAL signaling 38 .…”

Section: Introductionmentioning

confidence: 99%

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Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Sharma

Gnamlin

Durden

et al. 2019

Preprint

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Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence.This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a "fail-safe" mechanism to prevent expansion of malignant cells to prevent further injury.Upon removal of the "stress" conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-noncoding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse.In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors. 25, 26 . We and others have shown that CD133+ population are generally slow-cycling or quiescent 2, 6, 36 . This indicates that the cell cycle plays an active role in maintenance of this population in a quiescent and slow cycling state.Growth Arrest Specific 5 or GAS5, is a long non-coding RNA regulates cell cycle in a number of mammalian systems including several cancers 7, 15, 16, 23 . It also mediates cell proliferation by regulating CDK6 activity 17 . Studies have also shown that GAS5 forms a positive feedback network with a number of genes involved in self-renewal like Sox2/Oct4, making this long noncoding RNA (LncRNA) a critical player in induction and maintenance of the "stemness" state in a tumor 34 . GAS5 is further involved in regulation of human embryonic stem cell self-renewal by maintaining NODAL signaling 38 . Mechanistically, the effect of GAS5 on cell cycle is regulated by its interaction with the glucocorticoid receptor (GR) 11 . GRs are nuclear receptor proteins that control cell proliferation via their effect on cell cycle 30 . GAS5 interacts with the activated GR

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Sharma

Gnamlin

Durden

et al. 2019

Preprint

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“…LncRNA as an important regulator, is involved in multiple functions, including cell growth and pluripotency in mESCs. For example, lncRNA Gas5 is required for the maintenance of mESCs self-renewal and proliferation through interactions with pluripotent transcriptional factors and DNA demethylation regulators (Tu et al, 2018). LncRNA Trincr1 binds TRIM71 to inhibit its SHCBP1 stabilizing activity, and then sensitizes mESCs to depend on Trim71 for rapid proliferation (Li et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

lncRNA 5430416N02Rik Promotes the Proliferation of Mouse Embryonic Stem Cells by Activating Mid1 Expression through 3D Chromatin Architecture

et al. 2020

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Both 3D chromatin architecture and long non-coding RNAs (lncRNAs) play essential roles in pluripotency maintenance. However, whether lncRNAs are involved in organizing 3D chromatin structure remains largely unexplored. We identified 39 lncRNAs bound by Klf4, among which we further revealed the 5430416N02Rik promoter is a chromatin interaction hub. Knockout of the 5430416N02Rik locus reduces the proliferation rate of embryonic stem cells (ESCs). Moreover, deleting both the promoter and the gene body of 5430416N02Rik causes a more severe proliferation defect and has a more profound impact on the transcriptome than deleting the gene body alone. The reduced proliferation of the 5430416N02Rik locus knockout ESCs is mainly due to the downregulation of Mid1, the expression of which requires the inter-chromosomal interaction between Mid1 and 5430416N02Rik loci. In summary, our data demonstrated that the lncRNA 5430416N02Rik gene locus maintains the fast proliferation of ESCs by activating the expression of Mid1 through chromatin interaction.

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“…These many variants of Gas5 suggest that this gene has a key role in preimplantation embryo development. Previous reports on Gas5 described that it is related to the self-renewal and pluripotency of stem cells [34,35], and it can also act as a competing endogenous RNA (ceRNA) to exert its functions. Furthermore, we found that the expression of AS genes was significantly different in the two-cell stage compared with other stages in preimplantation embryo development (Fig.…”

Section: Difference Of Alternative Splicing Types In Preimplantation mentioning

confidence: 99%

Alternative splicing signatures in preimplantation embryo development

Tian¹,

Li²,

Wu³

2020

Cell Biosci

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Background: Preimplantation embryo development is a highly ordered sequence of processes and it requires a precise temporal and spatial control of gene expression. Alternative splicing (AS) is a crucial process that changes the genomic instructions into functional proteins, playing a critical role in the regulation of gene expression. Therefore, studies of AS can significantly improve our understanding of transcription and splicing events in preimplantation embryo development. Results: To study signatures of AS in embryo development, we firstly identified the critical stage for gene transcription during the preimplantation embryo development. By analyzing single cells RNA-seq (scRNA-seq) data, we found that the two-cell stage is a critical stage for gene transcription in preimplantation embryo development. Further study showed that AS was widespread in preimplantation embryo development, especially at the two-cell stage. In combination with high-throughput chromosome conformation (Hi-C) data, we demonstrated that AS genes were highly enriched in TAD boundaries, while they had no relationship with the A/B compartment and TAD. Conclusion: Our results provide new insight into the relationship among AS, gene transcription and chromatin structure in preimplantation embryo development.

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Gas5 is an essential lncRNA regulator for self-renewal and pluripotency of mouse embryonic stem cells and induced pluripotent stem cells

Cited by 48 publications

References 29 publications

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

lncRNA 5430416N02Rik Promotes the Proliferation of Mouse Embryonic Stem Cells by Activating Mid1 Expression through 3D Chromatin Architecture

Alternative splicing signatures in preimplantation embryo development

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