Long non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling

Abstract

Long non-coding RNAs (lncRNAs) are known players in the regulatory circuitry of the self-renewal in human embryonic stem cells (hESCs). However, most hESC-specific lncRNAs remain uncharacterized. Here we demonstrate that growth-arrest-specific transcript 5 (GAS5), a known tumour suppressor and growth arrest-related lncRNA, is highly expressed and directly regulated by pluripotency factors OCT4 and SOX2 in hESCs. Phenotypic analysis shows that GAS5 knockdown significantly impairs hESC self-renewal, but its overexpression significantly promotes hESC self-renewal. Using RNA sequencing and functional analysis, we demonstrate that GAS5 maintains NODAL signalling by protecting NODAL expression from miRNA-mediated degradation. Therefore, we propose that the above pluripotency factors, GAS5 and NODAL form a feed-forward signalling loop that maintains hESC self-renewal. As this regulatory function of GAS5 is stem cell specific, our findings also indicate that the functions of lncRNAs may vary in different cell types due to competing endogenous mechanisms.

Modulation of specific cell cycle phases in human embryonic stem cells by lncRNA RNA decoys

“…Among the enriched pathways, we focused our analysis on the G1‐S cell cycle phase transition, because this is known to play a major role in ESC stemness . Moreover, there are few reports on the involvement of lncRNAs in cell cycle regulations of hESCs …”

“…Lin et al showed that Tcl1 upstream neuron‐associated lincRNA, or megamind (TUNA) plays a vital role in pluripotency of mouse ESCs by regulating the expressions of core pluripotent TFs (SOX2 and NANOG) which was further supported by Jacobs et al Another lncRNA, Linc‐ROR was reported to function as a competing endogenous RNA (ceRNA) and promote the expressions of 3 core pluripotent TFs, OCT4, SOX2, and NANOG, via interacting with hsa‐miR‐145‐5p to regulate self‐renewal of hESCs . Gas5, a growth arrest‐related lncRNA, was also seen to control self‐renewal of hESCs, which is directly regulated by OCT4 and SOX2 . Further, studies have shown that lncRNAs play important roles in regulating hESC‐specific transcriptional activation of genes by controlling posttranscriptional regulations by acting as miRNA sponge or by facilitating epigenetic modification via contributing to the functioning of chromatin modifiers .…”

“…Unlike mRNAs, lncRNAs lack well‐structured open reading frames (ORFs) and are less conserved compared to mRNAs and other small ncRNAs . lncRNAs are implicated in key biological processes such as stem cell pluripotency, differentiation, chromosomal conformation, imprinting genomic loci, and allosteric regulation of enzyme activity, and their aberrant expression is correlated with various pathophysiological states . They play these functions by modulating gene transcription through promoter modifications or inhibiting the nuclear localization of specific transcription factors (TFs), chromatin structure, and mRNA stability …”

Noncoding RNAs: Potential players in the self‐renewal of mammalian spermatogonial stem cells

“…In addition, several signaling pathways have been shown to play important roles in controlling self‐renewal of SSCs, including MEK–ERK, PI3K–Akt, Wnt–β‐catenin, and JAK–STAT signaling (Golestaneh et al, ; Hasegawa, Namekawa, & Saga, ; J. Lee et al, ; Tulina & Matunis, ). In recent years, regulatory noncoding RNAs (ncRNAs), such as microRNA (miRNA), long ncRNA (lncRNA), piwi‐interacting RNA (piRNA) and circular RNAs (circRNAs), has been observed to be involved in regulating the self‐renewal through forming an intricate regulatory network together with protein‐coding gene in different types of stem cells, including embryonic stem cells (ESC), induced pluripotent stem cells, cancer stem cells and adult stem cells including SSCs (S. Hu & Shan, ; Rosa & Ballarino, ; Wang et al, ; Xu et al, ).…”

Long non-coding RNAs: new players in mammalian female gametogenesis

“…GAS5 is the host gene of 11 human small nucleolar RNAs (snoRNA) involved in the 2'-O-methylation of rRNA. This lncRNA seems to be involved in embryogenesis, in fact, it increases OCT4, NANOG and SOX2 expression by Nodal regulation and is directly regulated by these stemness factors in hESCs, forming a circuit that promotes pluripotency (33). It has been demonstrated that ncRNAs are able to control different points of embryogenesis such asmaternal-zygotic transition, maintenance of pluripotencythe patterning of the body axes, specification and differentiation of cell types and organ morphogenesis (34).…”