- Open Access
The miR-290-295 cluster as multi-faceted players in mouse embryonic stem cells
© The Author(s) 2017
- Received: 12 June 2017
- Accepted: 1 August 2017
- Published: 7 August 2017
Increasing evidence indicates that embryonic stem cell specific microRNAs (miRNAs) play an essential role in the early development of embryo. Among them, the miR-290-295 cluster is the most highly expressed in the mouse embryonic stem cells and involved in various biological processes. In this paper, we reviewed the research progress of the function of the miR-290-295 cluster in embryonic stem cells. The miR-290-295 cluster is involved in regulating embryonic stem cell pluripotency maintenance, self-renewal, and reprogramming somatic cells to an embryonic stem cell-like state. Moreover, the miR-290-295 cluster has a latent pro-survival function in embryonic stem cells and involved in tumourigenesis and senescence with a great significance. Elucidating the interaction between the miR-290-295 cluster and other modes of gene regulation will provide us new ideas on the biology of pluripotent stem cells. In the near future, the broad prospects of the miRNA cluster will be shown in the stem cell field, such as altering cell identities with high efficiency through the transient introduction of tissue-specific miRNA cluster.
- miR-290-295 cluster
- Embryonic stem cells
- Pluripotency regulation
- Induced pluripotent stem cells
- Tumourigenesis and senescence
microRNAs (miRNAs) are about 22 nucleotide (nt) endogenously non-coding RNAs that negatively regulate the expression of various target genes at the post-transcriptional level. Currently, in the human genome, it is reported that there are ~1500 miRNAs and each miRNA potentially modulates hundreds of target genes [1, 2]. miRNAs play important roles in various signaling pathway regulation, such as metabolism, proliferation, apoptosis, differentiation and the development of tumor.
Gene clusters are generally composed of more than two related genes which are closely located on a chromosome, and they usually share sequence similarity . Increasing evidence suggests that clustered miRNA genes are generally located in a polycistron [4, 5], and co-expressed with neighboring miRNAs . From the consistent expression of most miRNA clusters, it is speculated that homologous miRNA clusters may share common cis-regulatory elements, resulting in a cooperative effect for those clusters. On the other hand, for the inconsistent expression of some miRNA clusters, perhaps have different transcriptional or maturation processes. Due to functional limitations, most miRNAs are highly conserved among species. Yu et al.  found that partial duplications from an ancestral gene often resulted in the formation of the miRNA clusters. In addition, tandem and segmental duplications were critical for the evolution of miRNA clusters. Compared with single miRNA in regulating a complex cell signaling network, the clustered miRNAs seemed more efficient and complicated.
In 1981, Evans et al.  isolated mouse embryonic stem cells (mESCs) for the first time, and in 1998, Thomson et al.  established human ESC cell line. Since then, the research field of the stem cells has developed rapidly. With the further study in the regulation mechanism of ESCs, Shinya Yamanaka  successfully got the induced pluripotent stem cells (iPSCs) by introducing transcription factors Oct4, Sox2, Klf4 and c-Myc into mouse fibroblasts in 2006. Meanwhile, it has been proposed that ESCs originate from the inner cell mass of mammalian blastocysts, and hold the promise of medical applications, such as tissue engineering and stem cell therapy, which becomes a hot spot in the field of stem cell research in recent years due to their ability to self-renew and differentiate into all kinds of cell types.
There are ESC-specific miRNA clusters in human and mouse, such as miR-302 and miR-371-373 clusters in human embryonic stem cells (hESCs), miR-302 and miR-290-295 clusters in mESCs. In fact, the miR-290-295 cluster is homolog of human miR-371-373, furthermore, the miR-302 and miR-290-295 clusters share the same seed sequence, as a result, they tend to have similar function in mESCs. But miR-290-295 cluster is highly expressed in mESCs compare to the miR-302 cluster. Dgcr8 is essential for the biogenesis of miRNAs, so knocking out of Dgcr8 results in the loss of all canonical miRNAs. It has been reported that the introduction of the miR-290-295 cluster members into the Dgcr8 −/− ESCs induces a highly transcriptionally homogenous population as well as wild-type ESCs [11, 12]. Furthermore, animals mostly die as embryo or infertile of female survivors when the miR-290-295 cluster is deleted [13–15], which shows the powerful features of the cluster. Therefore, it has become the focus of research. In recent years, it has been revealed that the miR-290-295 cluster plays an important role in the regulation of mESC pluripotent regulatory networks, differentiation, anti-apoptosis, as well as in the process of tumorigenesis and senescence in mouse embryonic fibroblasts. Therefore, intense research of miR-290-295 cluster will not only contribute to understanding the regulatory mechanisms in the early development of mESCs, but also help to explore the mechanisms of iPSCs and tumor regulation, so as to promote its application in the medical field.
ESC and iPSC self-renewals need to eliminate differentiation signal and obtain the pluripotency signal, in addition, the differentiation process trigger the closure of pluripotency procedure and the induction of lineage specification. Previously, the opinion is that regulating the pluripotent regulatory network is solely in a protein-centric approach, in recent years, however, the roles of miRNAs, especially the miR-290-295 cluster, attract more and more attention. Therefore, it will provide new insights for further study of miRNAs in the establishment and the maintenance of pluripotent regulation mechanisms of stem cells.
The miR-290-295 cluster promotes the process of MET
The miR-290-295 cluster affects the cell cycle phase distribution of ESCs
The miR-290-295 cluster regulates the expression of core transcription factors
The miR-290-295 cluster establishes and maintains pluripotency of stem cells by enhancing the expression of core transcription factors. The Oct4, Sox2, Klf4/Lin28, and c-Myc/Nanog are the core transcription factors of somatic cells reprogrammed into iPSCs. Lin28 was upregulated by transfection of miR-294 into Dicer-deficient cells, but the molecular mechanism is unknown . Judson et al.  showed the high inductive efficiency production of iPSCs with introduction of miR-290-295 cluster, and c-Myc was substituted for miR-294 successfully in somatic cell reprogramming. Thus, miR-294 is a downstream gene of c-Myc, and that miR-294 and c-Myc have some common downstream regulatory genes according to the prediction of GeneGo software, which can explain the ability of miR-294 to induce the pluripotent stem cells. The Wnt signaling pathway has been shown to be essential for maintaining pluripotency of stem cells [45, 46]. Dkk-1 has multiple roles in the cells, and the most prominent role is considered as an inhibitor of the Wnt signaling pathway . Zovoilis et al. demonstrated that the Dkk-1 was a direct target of miR-294 and miR-295, and the other members of the miR-290-295 cluster controlled Wnt or Dkk-1 activation indirectly . It is also confirmed that the overexpression of the miR-290-295 cluster increased c-Myc levels, which is a downstream target of the Wnt signaling pathway, while its inhibition had an opposite effect . So the miR-290-295 cluster upregulates the expression of c-Myc, but the exact molecular mechanism needs to be further explored. In addition, the miR-290-295 cluster promotes the re-activation of endogenous pluripotency factor Oct3/4 by repressing NR2F2 which is a transcriptional repressor of Oct3/4 . The miR-290-295 cluster also upregulates other pluripotency factors, such as N-myc, Sal4 (Fig. 2), but the specific molecular mechanism is still unclear [25, 43].
The miR-290-295 cluster regulates the metabolism of stem cells
The miR-290-295 cluster involves in epigenetic modifications mediated by PcG proteins
Intriguingly, it is known that the miR-290-295/302 clusters have also been shown to promote pluripotency in different circumstances, but how the same miRNAs possess two opposite functions remains unresolved. It is possible that the context-dependent function of the clusters in different developmental stages determines the outcome of the activity of some signaling pathways.
Recent studies have shown that the miR-290-295 cluster plays an important role in cell apoptosis. Zheng et al.  found that the miR-290-295 cluster protected mESC cells from apoptosis during exposure to genotoxic stress through gain and loss of function studies. Further study demonstrated that the miR-290-295 cluster targeted Caspase 2 and Ei24 resulting in preventing from apoptosis of mESC gene toxicity stress through inhibiting their expression. It is the first time to link the miR-290-295 cluster with apoptosis. Ei24 promotes cell death by binding to Bcl2 , while Caspase 2 is an important regulatory gene in apoptosis. Subsequently, Guo et al. showed that miR-290-295/miR-302 clusters downregulated apoptosis-promoting factors Bhlhe40, Casp8, Ikbkg, Perp, on the other hand, they also upregulated the apoptosis-inhibiting factor Aven under the condition of let-7c-induced apoptosis . In addition, Caspase 2 and Ei24 act as tumor suppressor genes, and their loss may contribute to tumor metastasis. For example, knockout of Ei24 in mouse fibroblasts or human breast cancer cell line, results in increasing resistance to etoposide induced apoptosis . Therefore, the miR-290-295 cluster was presumed to be tumorigenic. Moreover, the miR-371-373 cluster, that is the homologue of the human miR-290-295 cluster, has been found to be highly expressed in various tumors [77–79] and to promote malignant transformation [80, 81]. Therefore, it is reasonable to speculate that this cluster has a dual role, on the one hand, it helps to protect against harmful physiological stress during development in normal cells; on the other hand, it makes cancer cells to resist the genetic toxicity of chemotherapeutic drugs.
Except for a critical role in maintaining pluripotency of stem cells, the activation of Wnt signaling pathway also occurs in various of human cancers [90, 91]. It is reported that miR-372 and miR-373 activate Wnt signaling by targeting Dkk-1, which promotes the invasive activity of tumor cells . However, in hESCs, it is not reported yet whether miR-371-373 cluster maintains the pluripotency of stem cells through the activation of the Wnt signaling pathway or not. miR-373 has also been reported to promote tumor invasion and metastasis by suppression of CD44 . Moreover, miR-373 drives the EMT and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer , but in ESCs, the miR-371-373 cluster might also maintain pluripotency by promoting MET.
KY and W-BA contributed equally to this work and wrote the manuscript. L-YW gave some helps for this work. XT and J-FW revised and approved the article prior to its being submitted for publication. All authors read and approved the final manuscript.
The authors thank Shan-Bing Yin for English language editing. We are thankful for the financial support of the National Natural Science Foundation of China (Grant Number: 81670555). We are also thankful for John Wiley & Sons, Inc. and Yang Cao, et al. about permission us to use Fig. 4 in this review.
The authors declare that they have no competing interests.
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