PRDM14 Ensures Naive Pluripotency through Dual Regulation of Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells

Yamaji, Masashi; Ueda, Junji; Hayashi, Kozaburo; Ohta, Hiroshi; Yabuta, Yukihiro; Kurimoto, Kazuki; Nakato, Ryuichiro; Yamada, Yasuhiro; Shirahige, Katsuhiko; Saitou, Mitinori

doi:10.1016/j.stem.2012.12.012

Cited by 280 publications

(337 citation statements)

References 48 publications

(76 reference statements)

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“…61 Mad2l2 and Prdm14, on the other hand, are required for both the stable development of PGCs in early embryos, and for the propagation of ESCs in LIF/ serum. However, while Prdm14 functions at least partially in DNA methylation via DNMTs, 21 our transcriptional profiling did not provide evidence for such a function of Mad2l2. Rather, it appears that Mad2l2 functions both in ESCs and PGC development by affecting specific epigenetic signatures.…”

Section: Mad2l2contrasting

confidence: 71%

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Destabilization of pluripotency in the absence of Mad2l2

et al. 2015

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The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2¡/¡ ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm. However, they could be stably propagated using small molecule inhibitors of MAPK signaling. Several components of the MAPK cascade were up-or downregulated even in undifferentiated Mad2l2 ¡/¡ ESCs. Global levels of repressive histone H3 variants were increased in mutant ESCs, and the epigenetic signatures on pluripotency-, primitive endoderm-, and MAPK-related loci differed. Thus, H3K9me2 repressed the Nanog promoter, while the promoter of Gata4 lost H3K27me3 and became de-repressed in LIF/serum condition. Promoters associated with genes involved in MAPK signaling also showed misregulation of these histone marks. Such epigenetic modifications could be indirect consequences of mutating Mad2l2. However, our previous observations suggested the histone methyltransferases as direct (G9a) or indirect (Ezh2) targets of Mad2l2. In effect, the intricate balance necessary for pluripotency becomes perturbed in the absence of Mad2l2.

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Section: Mad2l2contrasting

confidence: 71%

“…20,21 This may correspond with the remarkable potential of PGCs from early post-implantation embryos to become pluripotent in vitro under LIF/2i conditions. 22 The resulting embryonic germ cells are indistinguishable from ESCs.…”

Section: Introductionmentioning

confidence: 90%

Destabilization of pluripotency in the absence of Mad2l2

et al. 2015

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“…mESCs maintained either in a conventional serum/LIF condition or in a ground state 2i condition are considered to exhibit a naïve state of pluripotency (Bradley et al 1984;Smith 2009, 2011). Ground state mESCs have a more homogenous transcriptional and morphological profile and exhibit higher expression of pluripotency genes, including Nanog and Prdm14, than conventional mESCs (Chambers et al 2007;Yamaji et al 2013). Initial experiments on Nanog suggested that the control of pluripotency is determined by biallelic expression in the ground state 2i condition versus monoallelic expression in the conventional serum/LIF condition (Miyanari and Torres-Padilla 2012).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation

et al. 2016

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Pluripotency, differentiation, and X Chromosome inactivation (XCI) are key aspects of embryonic development. However, the underlying relationship and mechanisms among these processes remain unclear. Here, we systematically dissected these features along developmental progression using mouse embryonic stem cells (mESCs) and single-cell RNA sequencing with allelic resolution. We found that mESCs grown in a ground state 2i condition displayed transcriptomic profiles diffused from preimplantation mouse embryonic cells, whereas EpiStem cells closely resembled the post-implantation epiblast. Sex-related gene expression varied greatly across distinct developmental states. We also identified novel markers that were highly enriched in each developmental state. Moreover, we revealed that several novel pathways, including PluriNetWork and Focal Adhesion, were responsible for the delayed progression of female EpiStem cells. Importantly, we "digitalized" XCI progression using allelic expression of active and inactive X Chromosomes and surprisingly found that XCI states exhibited profound variability in each developmental state, including the 2i condition. XCI progression was not tightly synchronized with loss of pluripotency and increase of differentiation at the single-cell level, although these processes were globally correlated. In addition, highly expressed genes, including core pluripotency factors, were in general biallelically expressed. Taken together, our study sheds light on the dynamics of XCI progression and the asynchronicity between pluripotency, differentiation, and XCI.

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“…Cytosine methylation is perhaps the most intensively studied of these modifications. A low level of cytosine methylation (<30% of CpG dinucleotides) is one of the few features that distinguish the most basal stem cells of the body-naïve embryonic stem cells (nESCs)-from stem cells primed for differentiation (1)(2)(3)(4)(5) or committed to somatic lineages (70-85% CpG methylation) (6,7). Importantly, inhibitors of the DNA methylation maintenance machinery can accelerate the reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) (8,9).…”

mentioning

confidence: 99%

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

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Meyenn

Ravichandran

et al. 2016

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

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Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe 2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

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PRDM14 Ensures Naive Pluripotency through Dual Regulation of Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells

Cited by 280 publications

References 48 publications

Destabilization of pluripotency in the absence of Mad2l2

Destabilization of pluripotency in the absence of Mad2l2

Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

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