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Wnt/β-catenin signaling pathway safeguards epigenetic stability and homeostasis of mouse embryonic stem cells.

ABSTRACT: Wnt/β-catenin signaling regulates both mouse embryonic stem cell (mESC) self-renewal and differentiation. Here we show that the activity of the Wnt/β-catenin signaling pathway safeguards normal DNA methylation of mESCs. Indeed, loss of Wnt activity correlated with loss of DNA methylation, especially at the imprinting control regions (ICRs) in prolonged in vitro mESC cultures. To address the role of Wnt signaling on ICR methylation we performed Reduced Representation Bisulfite Sequencing (RRBS) on both “Young” and “Old” mESCs, being at early and late passages, respectively. We found that several ICRs (both maternal and paternal) showed loss of methylation in “Old” cells that correlates with lower Wnt downstream target expression and lower β-catenin protein level, when compared to “Young” mESCs. In parallel, we analyzed the ICR methylation level also in two Wnt mutant clones after prolonged in vitro culture (O-S33Y #1 and #2). The mutant clones maintained high Wnt activity with passages, similar to “Young” mESCs and ICR methylation level at around 50%, further supporting the beneficial role of Wnt/β-catenin pathway on mESC epigenetic stability and homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE109417 | GEO | 2019/02/07

REPOSITORIES: GEO

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Canonical Wnt pathway controls mESCs self-renewal through inhibition of spontaneous differentiation via β-catenin/TCF/LEF functions

Project description:The Wnt/β-catenin signalling pathway is a key regulator of embryonic stem cell self-renewal and differentiation. Constitutive activation of this pathway has been shown to significantly increase mouse embryonic stem cell (mESC) self-renewal and pluripotency marker expression. In this study, we generated a novel β-catenin knock-out model in mESCs by using CRISPR/Cas9 technology to delete putatively functional N-terminally truncated isoforms observed in previous knock-out models. While we showed that aberrant N-terminally truncated isoforms are not functional in mESCS, we observed that canonical Wnt signalling is not active in mESCs, as β-catenin ablation does not alter mESC transcriptional profile in LIF-enriched culture conditions; on the other hand, Wnt signalling activation represses mESC spontaneous differentiation. We also showed that transcriptionally silent β-catenin (ΔC) isoforms can rescue β-catenin knock-out self-renewal defects in mESCs, cooperating with TCF1 and LEF1 in the inhibition of mESC spontaneous differentiation in a Gsk3 dependent manner.

2020-01-10 | GSE143340 | GEO

Efficient induction of Gcm1 under folate deficiency promotes vertebrate neural development by Wnt/β-catenin pathway activation

Project description:Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway leads to defective anteroposterior patterning, resulting in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We report here that in C57BL/6C mouse embryonic stem cells (mESC), folate deficiency activates Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promotes the formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex to regulate the Wnt target gene transactivation through the Wnt-responsive elements. Moreover, the enhanced transcriptional activity of Gcm1 is found to be dependent on CREB binding protein. Lastly, in NTDs mouse models and low folate NTDs human brain samples, Gcm1 and Wnt/β-catenin target genes related to neural tube closure are specifically overexpressed. These results indicate that low folate promotes Wnt/β-catenin signaling via activating Gcm1, leading to aberrant vertebrate neural development

2018-12-27 | GSE124339 | GEO

Cell signaling coordinates global Polycomb Repressive Complex 2 recruitment and developmental gene expression in murine embryonic stem cells (ChIP-Seq)

Project description:In this study, we provide evidence to show that the expression of PRC2-recruting factor Jarid2 is largely reduced in both naïve mESC and Erk1/Erk2 double knockout (Erk1/2-dKO) mESCs, which can be rescued by reactivation of FGF/MARK signaling in naïve mESCs or ectopic Erk1 expression in Erk1/2-dKO mESCs, suggesting the FGF/ERK signaling positively regulates the Jarid2 expression in mESCs. Consistent with the Jarid2 function in the PRC2 recruitment, the global Ezh2 occupancy and histone H3K27me3 are largely reduced at CpG islands (CGIs) and bivalent promoters in both naïve mESCs and Erk1/Erk2-dKO mESCs, which can be fully restored by ectopic expression of Jarid2 expression, suggesting the reduced Jarid2-mediated PRC2 recruitment is a main molecular mechanism leading to the global reduction of PRC2 occupancy at CpG islands and bivalent promoters in naïve mESCs. At the transcriptional level, although both PRC2 occupancy and histone H3K27me3 modification are reduced at bivalent promoters, there exist two groups of genes with distinct expression status. the FGF/ERK signaling target genes are silenced while the Wnt signaling target genes are largely de-repressed, which is caused by the chemical activation of Wnt/beta-catenin signaling in naïve mESCs. Further ChIP-seq analyses demonstrate an increased occupancy of β-catenin at its activated gene promoters in naïve mESCs. These results suggest the transcriptional activation of bivalent genes in naïve mESCs is predominantly determined by the presence of transcriptional factors but not the status of PRC2 occupancy at gene promoters.

2020-10-13 | GSE157748 | GEO

Cell signaling coordinates global Polycomb Repressive Complex 2 recruitment and developmental gene expression in murine embryonic stem cells (RNA-Seq)

2020-10-13 | GSE157747 | GEO

De novo DNA methylation at imprinted loci during reprogramming into naïve and primed pluripotency

Project description:CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during the somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, were often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs.

2019-06-18 | GSE111173 | GEO

DNA sequence determines epigenetic bistability at imprinting control regions [BS-Seq]

Project description:Genomic imprinting is regulated by parental-specific epigenetic marks that differentiate between maternal and paternal chromosomes. Despite identical DNA sequence, the presence or absence of DNA methylation leads to the establishment of two distinct epigenetic states at Imprinting Control Regions (ICR). Here we combine targeted epigenome engineering to generate ectopic loci in the mouse embryonic stem cell genome that recapitulate the epigenetic properties of ICRs. We describe these ectopic ICRs as strong cis-regulatory sequences that can adopt and memorise one of two opposing epigenetic states, dependent of pre-imposed DNA methylation. This bistability is unique to ICRs and enabled us to systematically study the genetic and epigenetic determinants required for creating and maintaining the observed states. Through sequence manipulation we show that the ICR DNA sequence confers autonomy of ICRs and is required for creating epigenetic bistability. Genetic screens using DNA-methylation-sensitive reporters identify key components involved in regulating maintenance of epigenetic states. Besides DNMT1, UHRF1 and ZFP57, we identify novel factors that prevent switching between methylated and unmethylated states and validate two of these candidates, ATF7IP and ZMYM2, to be important for epigenetic memory at ICRs. In summary we show that the DNA sequence of ICRs provides the prerequisite for establishment of two distinct epigenetic states, while DNA and histone modifications ensure their stable propagation.

2022-07-20 | GSE176460 | GEO

DNA sequence determines epigenetic bistability at imprinting control regions [ChIP-Seq]

2022-07-20 | GSE176459 | GEO

DNA sequence determines epigenetic bistability at imprinting control regions [WGBS]

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The beta-catenin interactome in a vascular smooth muscle cell model

Project description:Canonical Wnt/β-catenin signalling is an essential regulator of various cellular functions throughout development and adulthood. Aberrant Wnt/β-catenin signalling also contributes to various pathologies including cancer, necessitating an understanding of cell context dependent mechanisms regulating this pathway. Since protein-protein interactions underpin β-catenin function and localization, we sought to identify novel β-catenin interacting partners by affinity purification coupled with tandem mass spectrometry in vascular smooth muscle cells (VSMCs), where β-catenin is involved in both physiological and pathological control of cell proliferation. Here, we report novel components of the VSMC β-catenin interactome.

2018-10-25 | PXD010421 | Pride

Characterisation of the Beta-Catenin cytoplasmic/nuclear interactome in leukaemia cells

Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.

2019-01-11 | PXD009305 | Pride

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