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ETO Family Protein Mtgr1 Mediates Prdm14 Functions in Stem Cell Maintenance

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE74547 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA300681

REPOSITORIES: GEO

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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. Examination of Prdm14 and Mtgr1 occupancy by ChIP-seq and effects on gene expression in mouse embryonic stem cells

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

Germline development in rat revealed by visualization and deletion of Prdm14

Project description:Primordial germ cells (PGCs), the founder cells of the germline, are specified in pre-gastrulating embryos in mammals, and subsequently migrate towards gonads to mature into functional gametes. Here, we investigated PGC development in rats, by genetically modifying Prdm14, a unique marker and a critical PGC transcriptional regulator. We trace PGC development in rats, for the first time, from specification until sex determination stage in fetal gonads using Prdm14 H2BVenus knock-in rats. We uncover that Prdm14’s crucial role in PGC specification is conserved between rat and mice, by analyzing Prdm14 deficient rat embryos. Notably, loss of Prdm14 completely abrogates the PGC program: failure in maintenance and/or activation of germ cell markers and pluripotency genes. Finally, we profile the transcriptome of the postimplantation epiblast and all PGC stages in rat, to reveal enrichment of distinct gene sets at each transition point, thereby providing an accurate transcriptional time-line for rat PGC development. Thus, the novel genetically modified rats and data sets obtained in this study will advance our knowledge on conserved vs species-specific features for germline development in mammals.

2019-12-26 | GSE135388 | GEO

Genome-wide mapping of PRDM14 binding sites in human embryonic stem cells

Project description:PRDM14 belongs to the PR (PRDI-BF1 and RIZ) domain proteins (PRDM) family which is a subclass of the SET domain proteins, a common domain found in histone modifying enzymes. PRDM14 has been previously implicated to regulate self-renewal of hESCs as knock-down of PRDM14 induced expression of differentiation marker genes and altered the cellular morphology. We showed that PRDM14 directly regulates the expression of key pluripotency gene POU5F1. Genome-wide location profiling experiments revealed that PRDM14 co-localized extensively with other key transcription factors such as OCT4, NANOG and SOX2. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Hence, PRDM14 exemplifies a key transcription factor that is required for the maintenance of human ESC identity and the reacquisition of pluripotency in human somatic cells.

2010-10-20 | GSE22767 | GEO

Genome-wide mapping of PRDM14 binding sites in human embryonic stem cells

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A critical but divergent role of PRDM14 in human primordial germ cell fate revealed by inducible degrons [ChIP-seq]

Project description:PRDM14 is a crucial regulator of mouse primordial germ cells (mPGC), epigenetic reprogramming and pluripotency, but its role in the evolutionarily divergent regulatory network of human PGCs (hPGCs) remains unclear. Besides, a previous knockdown study indicated that PRDM14 might be dispensable for human germ cell fate. Here, we decided to use inducible degrons for a more rapid and comprehensive PRDM14 depletion. We show that PRDM14 loss results in significantly reduced specification efficiency and an aberrant transcriptome of human PGC-like cells (hPGCLCs) obtained in vitro from human embryonic stem cells (hESCs). Chromatin immunoprecipitation and transcriptomic analyses suggest that PRDM14 cooperates with TFAP2C and BLIMP1 to upregulate germ cell and pluripotency genes, while repressing WNT signalling and somatic markers. Notably, PRDM14 targets are not conserved between mouse and human, emphasising the divergent molecular mechanisms of PGC specification. The effectiveness of degrons for acute protein depletion is widely applicable in various developmental contexts.

2019-12-08 | GSE138674 | GEO

A critical but divergent role of PRDM14 in human primordial germ cell fate revealed by inducible degrons [RNA-seq]

2019-12-08 | GSE138673 | 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.

2015-04-06 | GSE53498 | GEO

Mus musculus

Project description:ETO Family Protein Mtgr1 Mediates Prdm14 Functions in Stem Cell Maintenance

| PRJNA300681 | ENA

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

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

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.

2016-11-18 | GSE77622 | GEO

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