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The Sm protein methyltransferase PRMT5, is not required for primordial germ cell specification in mice

ABSTRACT: PRMT5 is a type II protein arginine methyltransferase with roles in stem cell biology, reprogramming, cancer and neurogenesis. During embryogenesis in the mouse it was hypothesized that PRMT5 functions with the master germline determinant BLIMP1 to promote primordial germ cell (PGC) specification. Using a Blimp1-Cre germline conditional knockout, we discovered that Prmt5 has no major role in murine germline specification, or the first global epigenetic reprogramming event involving depletion of cytosine methylation from DNA and histone H3 lysine 9 dimethylation from chromatin. Instead, we discovered that PRMT5 functions at the conclusion of PGC reprogramming I to promote proliferation, survival and expression of the gonadal germline program as marked by MVH. We show that PRMT5 regulates gene expression by promoting methylation of the Sm spliceosomal proteins, and significantly altering the spliced repertoire of RNAs in mammalian embryonic cells and primordial cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE63800 | GEO | 2014/12/05

REPOSITORIES: GEO

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The Sm protein methyltransferase PRMT5, is not required for primordial germ cell specification in mice

Project description:PRMT5 is a type II protein arginine methyltransferase with roles in stem cell biology, reprogramming, cancer and neurogenesis. During embryogenesis in the mouse it was hypothesized that PRMT5 functions with the master germline determinant BLIMP1 to promote primordial germ cell (PGC) specification. Using a Blimp1-Cre germline conditional knockout, we discovered that Prmt5 has no major role in murine germline specification, or the first global epigenetic reprogramming event involving depletion of cytosine methylation from DNA and histone H3 lysine 9 dimethylation from chromatin. Instead, we discovered that PRMT5 functions at the conclusion of PGC reprogramming I to promote proliferation, survival and expression of the gonadal germline program as marked by MVH. We show that PRMT5 regulates gene expression by promoting methylation of the Sm spliceosomal proteins, and significantly altering the spliced repertoire of RNAs in mammalian embryonic cells and primordial cells. Examination of transcriptional profile of iPHet (Control) vs. iPKO (Prmt5 knock out) 2i Embryonic Stem Cells

2014-12-05 | E-GEOD-63800 | biostudies-arrayexpress

Investigations on the role of Blimp1 in pluripotency and reprogramming

Project description:Blimp1 (Prdm1), the key determinant of primordial germ cells (PGC), plays a combinatorial role with Prdm14 during PGC specification from postimplantation epiblast cells. They together initiate epigenetic reprogramming in early germ cells towards an underlying pluripotent state, which is equivalent to embryonic stem cells (ESC). Whereas Prdm14 alone can promote reprogramming and is important for the propagation of the pluripotent state, it is not known if Blimp1 is similarly involved. Using a genetic approach, we demonstrate that Blimp1 is dispensable for the derivation and maintenance of ESC and postimplantation epiblast stem cells (EpiSC). Notably, Blimp1 is also dispensable for reprogramming EpiSC to ESC. Thus, while Blimp1 is obligatory for PGC specification, it is not required for the reversion of EpiSC to ESC, and for their maintenance thereafter. This study suggests that reprogramming, including that of somatic cells to ESC, may not entail an obligatory route through Blimp1 positive PGC-like state.

2012-07-21 | GSE35983 | GEO

A mesodermal factor, T (Brachyury), specifies mouse germ cell fate by directly activating germline determinants

Project description:Germ cells ensure reproduction and heredity in metazoans. Primordial germ cells (PGCs) in mice are induced in pluripotent epiblasts by BMP4 and WNT3, yet their mechanism of action remains unclear. Here, using in vitro PGC specification system, we show that WNT3 induces many transcription factors associated with mesoderm in epiblast-like cells (EpiLCs) through b-CATENIN. Among these, T (BRACHYURY), a classical and conserved mesodermal factor, was essential for robust activation of Blimp1 and Prdm14, two of the germline determinants. T, but not SMAD1 or b-CATENIN/TCF1, binds distinct regulatory elements of both Blimp1 and Prdm14, and without BMP4 and WNT3, directly up-regulates these genes, consequently delineating downstream PGC program. Without BMP4, a program induced by WNT3 prevents T from activating Blimp1 and Prdm14, demonstrating that BMP4 is permissive for PGC specification. These findings establish a fundamental role of a mesodermal transcription factor in PGC specification, a potentially evolutionarily conserved mechanism across metazoans. Genome target search for transcription factors, SMAD1, T, and TCF1 on PGC-like cells

2013-12-11 | E-GEOD-50394 | biostudies-arrayexpress

A Mesodermal Factor, T (BRACHYURY), specifies mouse germ cell fate by directly activating germline determinants.

Project description:The germ cell lineage ensures reproduction and heredity in metazoans. Primordial germ cells (PGCs) in mice are induced in pluripotent epiblast cells by BMP4 and WNT3, yet their mechanism of action remains elusive. Here, using in vitro PGC specification system, we show that WNT3, but not BMP4, induces many transcription factors associated with mesoderm in epiblast-like cells (EpiLCs) through beta-CATENIN. Among these, T (BRACHYURY), a classical and conserved mesodermal factor, was essential for robust activation of Blimp1 and Prdm14, two of the germline determinants. T, but not SMAD1 or beta-CATENIN/TCF1, binds distinct regulatory elements of both Blimp1 and Prdm14, and directly up-regulates these genes without BMP4 and WNT3. Without BMP4, a program induced by WNT3 prevents T from activating Blimp1 and Prdm14, demonstrating that BMP4 is permissive for PGC specification. These findings establish a fundamental role of a mesodermal gene in PGC specification, a potentially evolutionarily conserved mechanism across metazoans. Wnt3 (+/+) and Wnt3 (-/-) mouse embryonic stem cells (mESCs) bearing the BV transgenes expressing membrane-targeted Venus under the control of Blimp1 regulatory elements (Blimp1-mVenus: BV; PMID 18583473) were established and maintained. Epiblast-like cells (EpiLCs) were then induced from the established ES lines, followed by the cytokine stimulation (No cytokines [negative control], BMP4, Wnt3a, BMP4+Wnt3a) for different periods (0h, 12h, 24h, 36h).

2013-12-11 | E-GEOD-49689 | biostudies-arrayexpress

A mesodermal factor, T (Brachyury), specifies mouse germ cell fate by directly activating germline determinants

2013-12-11 | GSE50394 | GEO

SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate

Project description:Specification of primordial germ cells (PGCs) marks the beginning of the totipotent state. However, without a tractable experimental model, the mechanism of human PGC (hPGC) specification remains unclear. Here, we demonstrate specification of hPGC-like cells (hPGCLCs) from germline competent pluripotent stem cells. The characteristics of hPGCLCs are consistent with the embryonic hPGCs and a germline seminoma that share a CD38 cell-surface marker, which collectively defines likely progression of the early human germline. Remarkably, SOX17 is the key regulator of hPGC-like fate, whereas BLIMP1 represses endodermal and other somatic genes during specification of hPGCLCs. Notable mechanistic differences between mouse and human PGC specification could be attributed to their divergent embryonic development and pluripotent states, which might affect other early cell-fate decisions. We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information. RNA-Seq analysis to investigate transcriptomes of hPGC-like cells (hPGCLCs), fetal hPGCs, TCam-2 and hESCs

2014-12-26 | E-GEOD-60138 | biostudies-arrayexpress

A Mesodermal Factor, T (BRACHYURY), specifies mouse germ cell fate by directly activating germline determinants.

2013-12-11 | GSE49689 | GEO

Human PGC commitment shares key gene dynamics to mouse, but owns a unique PRDM14 expression pattern

Project description:The molecular mechanisms of human primordial germ cell (PGC) specification are poorly understood due to the inaccessibility of cell materials and the lack of an alternative in vitro model that enables tracking of the earliest stages of germ cell development. Here, we introduce a defined and efficient differentiation system for the induction of pre-migratory PGC-like cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). By step-wise differentiation, we generated an OCT4+/ T+/BLIMP1+ cell population that transitioned into STELLA expressing PGC-like cells that exhibited a similar key gene expression as mouse PGCs as well as global epigenetic reprogramming. Even though, these PGC-like cells expressed PRDM14 at very low levels, they underwent activation of pluripotency/PGC genes, suppression of neural induction and suppression of de novo DNA methylation, events that are regulated by Prdm14 during mouse PGC specification. This study demonstrates that human PGC commitment shares many key features with mouse PGC specification, but harbors unique and so far unknown mechanisms that, point to a novel human transcriptional regulation. 7 samples were analyzed. ESC: Human Embryonic Stem Cells, 1 biological rep iPSC: Human induced Pluripotent Stem Cells, 1 biological rep d2: Human induced Pluripotent Stem Cells, 2 days differentiation treatment , 2 biological rep d4PGCLC: Human induced Pluripotent Stem Cells, 4 days differentiation treatment towards Primordial Germ Cells Like Cells, 1 biological rep d6PGCLC: Human induced Pluripotent Stem Cells, 6 days differentiation treatment towards Primordial Germ Cells Like Cells, 2 biological rep

2015-04-06 | E-GEOD-53498 | biostudies-arrayexpress

SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate

2014-12-26 | GSE60138 | GEO

Comparative principles of DNA methylation reprogramming during human and mouse in vitro primordial germ cell specification [Mouse and Human RNA-seq and BS-seq]

Project description:Primordial germ cell (PGC) development is characterized by global epigenetic remodeling, which resets genomic potential and establishes an epigenetic ground state. Here we recapitulate PGC specification in vitro from naive embryonic stem cells and characterize the early events of epigenetic reprogramming during the formation of the human and mouse germline. Following rapid de novo DNA methylation during priming to epiblast-like cells, methylation is globally erased in PGC-like cells (PGCLCs). Repressive chromatin marks (H3K9me2/3) and transposable elements are enriched at demethylation resistant regions, while active chromatin marks (H3K4me3 or H3K27ac) are more prominent at regions that demethylate faster. The dynamics of specification and epigenetic reprogramming show species-specific differences, in particular markedly slower reprogramming kinetics in the human germline. Differences in developmental kinetics between species may be explained by differential regulation of epigenetic modifiers. Our work establishes a robust and faithful experimental system of the early events of epigenetic reprogramming and its regulation in the germline.

2016-10-10 | GSE86903 | GEO

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