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

ABSTRACT: Mouse embryonic stem cells (mESCs) fluctuate between a naïve inner cell mass (ICM)-like state and a primed epiblast-like state of pluripotency in serum, but are harnessed exclusively in a distinctive, naïve state of pluripotency that more faithfully captures the ICM state (the ground state) with inhibitors for mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i). Understanding the mechanism ensuring the naïve states of pluripotency will be critical to realizing the full potential of ESCs. We show here that PRDM14, a PR domain-containing transcriptional regulator, ensures naïve pluripotency by a dual mechanism: Antagonizing fibroblast growth factor receptor (FGFR) signaling that is activated paradoxically by the core transcriptional circuitry for pluripotency and directs a primed state, and repressing de novo DNA methyltransferases that create a primed epiblast-like epigenome. PRDM14 exerts these functions by recruiting polycomb repressive complex 2 (PRC2) specifically to key targets and repressing their expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE42616 | GEO | 2013/01/18

SECONDARY ACCESSION(S): PRJNA182360

REPOSITORIES: GEO

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

Project description:Mouse embryonic stem cells (mESCs) fluctuate between a naïve inner cell mass (ICM)-like state and a primed epiblast-like state of pluripotency in serum, but are harnessed exclusively in a distinctive, naïve state of pluripotency that more faithfully captures the ICM state (the ground state) with inhibitors for mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i). Understanding the mechanism ensuring the naïve states of pluripotency will be critical to realizing the full potential of ESCs. We show here that PRDM14, a PR domain-containing transcriptional regulator, ensures naïve pluripotency by a dual mechanism: Antagonizing fibroblast growth factor receptor (FGFR) signaling that is activated paradoxically by the core transcriptional circuitry for pluripotency and directs a primed state, and repressing de novo DNA methyltransferases that create a primed epiblast-like epigenome. PRDM14 exerts these functions by recruiting polycomb repressive complex 2 (PRC2) specifically to key targets and repressing their expression. ChIP-seq of PRDM14 and that of H3K27me3 and SUZ12 on Prdm14 wildtype and knockout ES cells

2013-01-18 | E-GEOD-42616 | biostudies-arrayexpress

PRDM14 Ensures a Naïve Pluripotency by a Dual Mechanism Involving Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells

Project description:Mouse embryonic stem cells (mESCs) fluctuate between a naïve inner cell mass (ICM)-like state and a primed epiblast-like state of pluripotency in serum, but are harnessed exclusively in a distinctive, apparently more naïve state of pluripotency (the ground state) with inhibitors for mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i). Understanding the mechanism ensuring a naïve state of pluripotency would be critical in realizing a full potential of ESCs. We show here that PRDM14, a PR domain-containing transcriptional regulator, ensures a naïve pluripotency by a dual mechanism: Antagonizing fibroblast growth factor receptor (FGFR) signaling that is activated paradoxically by the core transcriptional circuitry for pluripotency and directs a primed state and repressing de novo DNA methyltransferases that create a primed epiblast-like epigenome. PRDM14 exerts these functions by recruiting polycomb repressive complex 2 (PRC2) specifically to key targets and repressing their expression. Mouse Embryonic Stem Cells (mESCs) or mESC-like cells with different Prdm14 genotypes {Prdm14(+/+), Prdm14(-/-), and Prdm14(-/-) rescued with Avitag-EGFP-Prdm14 transgene [Prdm14(-/-)+AGP14]} are cultured on MEF in different medium [2i, Serum(day 2), Serum+MEK inhibitor (PD0325901) (day 2), Serum without LIF (day2)].

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PRDM14 Ensures a Naïve Pluripotency by a Dual Mechanism Involving Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells

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PRDM14 drives OCT3/4 recruitment via active demethylation in the transition from primed to naïve pluripotency

Project description:Primordial germ cells (PGCs) are specified from epiblast cells in mice. Genes associated with naïve pluripotency are transiently repressed in the transition from inner cell mass (ICM) to epiblast cells, followed by their upregulation soon after PGC specification. However, the molecular mechanisms underlying the reactivation of pluripotency genes are poorly characterized. Here, we exploited in vitro differentiation of epiblast-like cells (EpiLCs) from embryonic stem cells (ESCs) to elucidate the molecular and epigenetic functions of PR domain-containing 14 (PRDM14). We found that Prdm14 overexpression in EpiLCs induced their conversion to ESC-like cells even in the absence of leukemia inhibitory factor (LIF). This was impaired by the loss of Kruppel-like factor 2 (Klf2) and ten-eleven translocation (TET) proteins. Furthermore, PRDM14 recruited OCT3/4 to the enhancer regions of naïve pluripotency genes via TET-base excision-repair-mediated demethylation. Our results provide evidence that PRDM14 establishes a transcriptional network for naïve pluripotency via active DNA demethylation.

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Expression data of PRDM14 overexpression in WT, Suz12 KO and Ctbp1/2 DKO ESCs

Project description:The pluripotency-associated transcriptional network is regulated by a core circuitry of transcription factors. The PR domain-containing protein, PRDM14, maintains pluripotency by activating and repressing transcription in a target gene-dependent manner. However, the mechanisms underlying dichotomic switching of PRDM14-mediated transcriptional control remains elusive. Here, we identified C-terminal binding protein 1/2 (CtBP1/2) as components of the PRDM14-mediated repressive complex. CtBP1/2 binding to PRDM14 depends on CBFA2T2, a core component of the PRDM14 complex. The loss of Ctbp1/2 impaired the PRDM14-mediated transcriptional repression required for pluripotency maintenance and primed to naïve pluripotency transition. Furthermore, CtBP1/2 also interacted with the PRC2 complexes, and the loss of Ctbp1/2 impaired the PRC2 and H3K27me3 enrichment at the target genes upon PRDM14 overexpression. These results suggest that evidence that the target gene-dependent transcriptional activity of PRDM14 is regulated by partner switching to ensure transition from primed to naïve pluripotency.

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ETO Family Protein Mtgr1 Mediates Prdm14 Functions in Stem Cell Maintenance

Project description:Prdm14 is a sequence-specific transcriptional regulator of embryonic stem cell (ESC) pluripotency and primordial germ cell (PGC) formation. It exerts its function, at least in part, through repressing genes associated with epigenetic modification and cell differentiation. Here, we show that this repressive function is mediated through an ETO-family co-repressor Mtgr1, which tightly binds to the pre-SET/SET domains of Prdm14 and co-occupies its genomic targets in mouse ESCs. Structure-guided point mutants abrogated the Prdm14-Mtgr1 association and disrupted Prdm14's function in mESC gene expression and PGC formation in vitro. Altogether, our work uncovers the molecular mechanism underlying Prdm14-mediated repression.

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2016-07-03 | E-GEOD-74547 | biostudies-arrayexpress

Expresssion data of Prdm14 KO ESCs expressing each orthologues.

Project description:Gene regulatory networks underlying cellular pluripotency are controlled by a core circuitry of transcription factors, including POU5F1 and NANOG in mammals. However, the evolutionary origin and transformation of pluripotency transcriptional networks have not been elucidated in deuterostomes. PR domain-containing protein 14 (PRDM14) is specifically expressed in pluripotent cells and germ cells, and is required for establishing embryonic stem cells (ESCs) and primordial germ cells (PGCs) in mice. Here, we compared the functions and expression patterns of PRDM14 orthologues within deuterostomes. Amphioxus PRDM14, zebrafish PRDM14, and the combination of sea urchin PRDM14 and CBFA2T compensated for disruption of the mouse Prdm14 gene in terms of maintaining mouse ESC pluripotency. Interestingly, Prdm14 was expressed in motor neurons, but not in germ cells in amphioxus embryos as observed in zebrafish embryos. Therefore, our results suggest that the integration of the PRDM14–CBFA2T complex into the transcriptional network for pluripotency may be essential for stabilizing pluripotency during the early amniote development.

2019-01-29 | GSE112904 | GEO

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Project description:Pluripotent cells emerge as a naïve founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) respectively represent the initial naïve and final primed phases of pluripotency. Here we investigated the intermediate formative stage. Using minimal exposure to specification cues, we derived stem cells from formative mouse epiblast. Unlike ES cells or EpiSCs, formative stem (FS) cells responded directly to germ cell induction. They colonised somatic tissues and germline in chimaeras. Whole transcriptome analyses showed similarity to pre-gastrulation formative epiblast. Signal responsiveness and chromatin accessibility features reflect lineage capacitation. Furthermore, FS cells showed distinct transcription factor dependencies, relying critically on Otx2. Finally, FS cell culture conditions applied to human naïve cells or embryos supported expansion of similar stem cells, consistent with a conserved staging post on the trajectory of mammalian pluripotency. This SuperSeries is composed of the SubSeries listed below.

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Capture of mouse and human stem cells with features of formative pluripotency [scRNA-seq]

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