ZFP982 confers mouse embryonic stem cell characteristics by regulating expression of Nanog, Zfp42, and Dppa3
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ABSTRACT:
PROVIDER: PRJNA593720 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10590675.fastq.gz | Fastqsanger.gz | |||
| SRR10590676.fastq.gz | Fastqsanger.gz | |||
| SRR10590677.fastq.gz | Fastqsanger.gz | |||
| SRR10590678.fastq.gz | Fastqsanger.gz | |||
| SRR10590679.fastq.gz | Fastqsanger.gz |
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Project description:Abstract Background: Understanding the genetic underpinnings of protein networks conferring stemness is of broad interest for basic and translational research. Methods: We used multi-omics analyses to identify and characterize stemness genes, and focused on the zinc finger protein 982 (Zfp982) that regulates stemness through the expression of Nanog, Zfp42, and Dppa3 in mouse embryonic stem cells (mESC). Results: Zfp982 was expressed in stem cells, and bound to chromatin through a GCAGAGKC motif, for example near the stemness genes Nanog, Zfp42, and Dppa3. Nanog and Zfp42 were direct targets of ZFP982 that decreased in expression upon knockdown and increased upon overexpression of Zfp982. We show that ZFP982 expression strongly correlated with stem cell characteristics, both on the transcriptional and morphological levels. Zfp982 expression decreased with progressive differentiation into ecto-, endo- and mesodermal cell lineages, and knockdown of Zfp982 correlated with morphological and transcriptional features of differentiated cells. Zfp982 showed transcriptional overlap with members of the Hippo signaling pathway, one of which was Yap1, the major co-activator of Hippo signaling. Despite the observation that ZFP982 and YAP1 interacted and localized predominantly to the cytoplasm upon differentiation, the localization of YAP1 was not influenced by ZFP982 localization. Conclusions: Together, our study identified ZFP982 as a transcriptional regulator of early stemness genes, and since ZFP982 is under the control of the Hippo pathway, underscored the importance of the context-dependent Hippo signals for stem cell characteristics. Keywords: Hippo pathway; Nanog; Pluripotency; Stemness; Yap1; ZFP982.
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Project description:Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies focused on epigenetic factors that affect ESC self-renewal and pluripotency. Through our laboratory's previous studies on ESCs pluripotency, we found that Dppa3, as a Naive state marker gene, is of great significance to the transformation of mESCs pluripotency. However, the influence of overexpression of Dppa3 in ESCs on mESCs status has not been determined. Our results show that overexpression of Dppa3 induces global DNA demethylation, which is beneficial to the maintenance of pluripotency, but its differentiation ability is significantly impaired. In mESCs, Dppa3 regulates mESCs pluripotency by inhibiting de novo methylation pathway, maintaining methylation pathway, promoting demethylation pathway Tet2, up-regulating active histone modification and down-regulating heterogeneous histone modification. The 2C-like state of ESCs recapitulates key aspects of the two-cell stage mouse embryo both phenotypically and molecular, which providing a cellular model to investigate the progress of ZGA. Our results found Dppa3 promote facilitate 2C-state conversion.
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Project description:Single Cell Microarray <br>E10.5 genital ridges (TM at E7.5) incubated in 0.5mM EDTA/ PBS for 20 minutes at 37ï¾°C were transferred to 2% BSA/ PBS. PGCs were collected from the genital ridges pierced with fine glass needles. Released PGCs were identified by their morphological characteristics and transferred into lysis buffer with a mouth pipette. PGCs were genotyped with the remaining genital ridges. The amplified cDNA library of each PGC was classified by qPCR-based expression analyses of Nanog, Oct4, and Stella/Dppa3 (Kurimoto et al., 2007). cDNAs were labeled by in vitro transcription (Affymetrix). The cRNAs were hybridized with the GeneChip Mouse Genome 430 2.0 Array (Affymetrix). Data were analyzed using the Microsoft Excel and MeV (multiple experimental viewer) software. <br>
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Project description:Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression of Dppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have a Dppa3 gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.
2020-10-12 | PXD019794 | Pride
Project description:Comparative transcriptome of SW1222 colorectal cancer (CRC) cells that overexpress or are depleted of DPPA3 to identify genes involved in regulating of the slow-cycling cancer cell properties to uncover the molecular mechanism of the non-mutational chemoresistant phenotype.
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Project description:LINE-1 DNA methylation levels in DPPA3 KO overexpressing DPPA3 mutants
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Project description:Extracellular vesicles (EVs) released by cells contain mRNAs, miRNAs, lncRNAs, lipids, and proteins, playing crucial roles in cell-cell communication. While full-length mRNA transcripts have been documented in EVs secreted by cancer cells, there are no reports on full transcripts secreted by embryos. Our study aimed to identify extracellular vesicle mRNAs in the culture media of bovine embryos and investigate their roles in embryo-mother communication. Following the isolation of EVs from in-vitro fertilization media samples and RNA sequencing, we identified full mRNA transcripts of three genes: SLBP2, ACCSL, and DPPA3. We selected DPPA3 for further investigation. To examine the role of DPPA3 in embryo-mother communication, an in vitro transcribed mRNA of DPPA3 was transfected into bovine endometrial epithelial cells. Transfected and control cells were subsequently analyzed for RNA sequencing to assess the effects of DPPA3 on gene expression. A total of 24 genes were found to be upregulated, and one gene was downregulated (FDR < 0.01) following DPPA3 transfection. Among the 18 annotated genes, 17 have known functions in pregnancy recognition in ruminants or have been previously identified as upregulated in pregnant animals. In addition to RNA sequencing, transfected and control cells underwent proteomic analysis. A total of 34 proteins were differentially expressed (FDR < 0.01, p < 0.05, fold change > 1.5), with 19 upregulated and 15 downregulated. Two proteins, ISG15 and MX1, overlapped with the differentially expressed mRNAs. To mimic the natural transfer of EVs from embryos to endometrial cells, we performed co-culture of day 8 blastocysts or supplemented the cells with embryo-conditioned culture media. DPPA3 expression was detected in endometrial cells exposed to embryo-conditioned media after just 30 minutes, with slight upregulation of ISG15 and MX1 also observed. The expression of these classic interferon-stimulated genes in endometrial cells increased from 0.5 to 10 hours when exposed to blastocysts or embryo-conditioned media. Overall, these results demonstrate that DPPA3 mRNA secreted from embryos may play a role in early embryo-mother communication and maternal recognition of pregnancy prior to major interferon tau secretion. Importantly, our study highlights the significant role of EVs in cell-cell communication through mRNA signaling from the embryo to the mother.
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Project description:Cellular reprogramming from somatic cells to induced pluripotent stem cells (iPSCs) can be achieved through forced expression of the transcription factors Oct4, Klf4, Sox2 and c-Myc (OKSM). These factors, in combination with environmental cues, induce a stable intrinsic pluripotency network that confers indefinite self-renewal capacity on iPSCs. In addition to Oct4 and Sox2, the homeodomain-containing transcription factor Nanog is an integral part of the pluripotency network. Although Nanog expression is not required for the maintenance of pluripotent stem cells, it has been reported to be essential for the establishment of both embryonic stem cells (ESCs) from blastocysts and iPSCs from somatic cells. Here we revisit the role of Nanog in direct reprogramming. Surprisingly, we find that Nanog is dispensable for iPSC formation under optimized culture conditions. We further document that Nanog-deficient iPSCs are transcriptionally highly similar to wild-type iPSCs and support the generation of teratomas and chimeric mice. Lastly, we provide evidence that the presence of ascorbic acid in the culture media is critical for overcoming the previously observed reprogramming block of Nanog knockout cells. Comparison of Nanog KO iPSCs to WT pluripotent cells.
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