A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells

Zheng, Grace X. Y.; Ravi, Arvind; Calabrese, J. Mauro; Medeiros, Lea A.; Kirak, Oktay; Dennis, Lucas; Jaenisch, Rudolf; Burge, Christopher B.; Sharp, Phillip A.

doi:10.1371/journal.pgen.1002054

Cited by 95 publications

(90 citation statements)

References 43 publications

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“…Moreover, miR-290-295 cluster is reported to be highly enriched in the germ cell population of day 6 testis when compared to the somatic cell population . This cluster is a target of pluripotency factors, and in turn targets the pluripotency factors Oct3/4, Sox2 and Nanog (Zheng et al, 2011). It is shown that suppression of the miR-290 cluster, besides embryonic lethality, leads to the defective migration of PGC numbers in the gonads.…”

Section: Mir-371-3mentioning

confidence: 99%

Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer

Eini¹,

Dorssers²,

Looijenga³

2013

Int. J. Dev. Biol.

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Section: Mir-371-3mentioning

confidence: 99%

Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer

Eini¹,

Dorssers²,

Looijenga³

2013

Int. J. Dev. Biol.

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“…[26][27][28] To check whether these miRs generally protect ESCs from apoptosis, we exposed ESCs transfected with anti-miRs to 5 Gy of X rays. In these conditions we observed increased apoptosis, as demonstrated by the accumulation of active caspase-3 ( Figure 4f).…”

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confidence: 99%

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

et al. 2014

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Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4. Cell Death and Differentiation (2015) 22, 1047-1057 doi:10.1038/cdd.2014; published online 5 December 2014ESCs represent a precious experimental model of the early stages of embryo development. They can be grown indefinitely in vitro and induced to differentiate, thus mimicking two events taking place in the blastocyst: (i) the differentiation of the cells of the inner cell mass into epiblast cells and (ii) the commitment of epiblast cells to neuroectodermal or mesendodermal precursors. 1,2 These differentiation events are regulated by extrinsic signals. BMP4, a member of the TGF-β superfamily of cytokines, has a crucial role in ESCs. Many results indicate that it is able, together with LIF, to maintain mouse ESCs in the pluripotent state. 3 This effect is mediated by the regulation of many direct targets of Smad1, 5 and 8, the transcription factors downstream of the BMP4 receptor. 4 BMP4 also contributes to govern early steps of differentiation. First, BMP4 acts by regulating ESC-epiblast transition and then by suppressing neural differentiation and promoting non-neural lineage formation. 2 Moreover, BMP4 promotes the differentiation towards mesendodermal lineages and also regulates, either positively or negatively, the further commitment of mesendodermal precursors into their different fates. [5][6][7][8] Gene expression in ESCs is regulated by a complex network of transcription factors. 9,10 In addition, numerous results indicate that miRNAs are crucial regulators of the gene expression programs that drive ESC differentiation. Suppression of miRNA biogenesis, obtained by knocking out Dicer or DCGR8 genes, leads to an early arrest of mouse embryonic development and of in vitro differenti...

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“…Thus, mouse-specific sequence variations in the 3′ UTRs of these genes gave rise to functional target sites. We additionally tested Caspase 2, a recently described miR-295 target with partially conserved target sites (28) and observed an 80% repression in response to transfection of miR-467a (Fig. 4D), indicating that these miRNAs can exert strong as well as moderate repression of targets.…”

Section: Target Sites Of Many Mouse-specific Sfmbt2 Cluster Mirnas Armentioning

confidence: 83%

“…While many of the identified target interactions are likely to be novel, a subset may functionally overlap with those of the miR-290-295 cluster which promotes proliferation (26) and survival (28). In some cases, single 3′ UTRs may be targeted by multiple cluster members, as was observed for Lats2 (a target of miR-467a and miR-466f-3p), a gene known to oppose proliferation and growth (32,34,35).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide impact of a recently expanded microRNA cluster in mouse

Zheng

Ravi

Gould

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Variations in microRNA (miRNA) gene and/or target repertoire are likely to be key drivers of phenotypic differences between species. To better understand these changes, we developed a computational method that identifies signatures of species-specific target site gain and loss associated with miRNA acquisition. Interestingly, several of the miRNAs implicated in mouse 3′ UTR evolution derive from a single rapidly expanded rodent-specific miRNA cluster. Located in the intron of Sfmbt2, a maternally imprinted polycomb gene, these miRNAs (referred to as the Sfmbt2 cluster) are expressed in both embryonic stem cells and the placenta. One abundant miRNA from the cluster, miR-467a, functionally overlaps with the mir-290-295 cluster in promoting growth and survival of mouse embryonic stem cells. Predicted novel targets of the remaining cluster members are enriched in pathways regulating cell survival. Two relevant species-specific target candidates, Lats2 and Dedd2, were validated in cultured cells. We suggest that the rapid evolution of the Sfmbt2 cluster may be a result of intersex conflict for growth regulation in early mammalian development and could provide a general model for the genomic response to acquisition of miRNAs and similar regulatory factors.

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A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells

Cited by 95 publications

References 43 publications

Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer

Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

Genome-wide impact of a recently expanded microRNA cluster in mouse

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