SUV39H2 CONTROLS TROPHOBLAST STEM CELL FATE
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA647264 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12266274_1.fastq.gz | Fastqsanger.gz | |||
| SRR12266274_2.fastq.gz | Fastqsanger.gz | |||
| SRR12266275_1.fastq.gz | Fastqsanger.gz | |||
| SRR12266275_2.fastq.gz | Fastqsanger.gz | |||
| SRR12266276_1.fastq.gz | Fastqsanger.gz |
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Project description:The placenta is constructed through the orchestration of trophoblast stem (TS) cell expansion and differentiation along a multi-lineage pathway. Dynamic regulation of histone H3K9 methylation is pivotal to cell differentiation for many cell lineages, but little is known about its involvement in trophoblast development. Among the twelve-known histone H3K9 methyltransferases, only SUV39H2 exhibited robust differential expression in stem versus differentiated rat TS cells. SUV39H2 transcript and protein expression were high in the stem state and rapidly declined as TS cells differentiated. Disruption of SUV39H2 expression in TS cells led to prominent phenotypic changes. Suv39h2-specific shRNA knockdown resulted in an arrest in TS cell proliferation and activation of trophoblast cell differentiation. These observations were reinforced by flow cytometry and transcript profiling. Histone H3K9 methylation status at specific loci exhibiting differentiation-dependent gene expression were regulated by SUV39H2 and also represented sites for SUV39H2 occupancy. Analyses of SUV39H2 on ex vivo rat blastocyst development supported its role in regulating TS cell expansion and differentiation. Finally, we identified SUV39H2 as a downstream target of CDX2, a master regulator of trophoblast lineage development. In summary, our findings indicate that SUV39H2 contributes to the maintenance of the TS cell stem state and restrains trophoblast cell differentiation and thus serves as a contributor to the epigenetic regulation of hemochorial placental development.
2021-07-15 | GSE154701 | GEO
Project description:BackgroundThe placenta is formed by the coordinated expansion and differentiation of trophoblast stem (TS) cells along a multi-lineage pathway. Dynamic regulation of histone 3 lysine 9 (H3K9) methylation is pivotal to cell differentiation for many cell lineages, but little is known about its involvement in trophoblast cell development.MethodsExpression of H3K9 methyltransferases was surveyed in rat TS cells maintained in the stem state and following differentiation. The role of suppressor of variegation 3-9 homolog 2 (SUV39H2) in the regulation of trophoblast cell lineage development was investigated using a loss-of-function approach in rat TS cells and ex vivo cultured rat blastocysts.ResultsAmong the twelve-known H3K9 methyltransferases, only SUV39H2 exhibited robust differential expression in stem versus differentiated TS cells. SUV39H2 transcript and protein expression were high in the stem state and declined as TS cells differentiated. Disruption of SUV39H2 expression in TS cells led to an arrest in TS cell proliferation and activation of trophoblast cell differentiation. SUV39H2 regulated H3K9 methylation status at loci exhibiting differentiation-dependent gene expression. Analyses of SUV39H2 on ex vivo rat blastocyst development supported its role in regulating TS cell expansion and differentiation. We further identified SUV39H2 as a downstream target of caudal type homeobox 2, a master regulator of trophoblast lineage development.ConclusionsOur findings indicate that SUV39H2 contributes to the maintenance of TS cells and restrains trophoblast cell differentiation.General significanceSUV39H2 serves as a contributor to the epigenetic regulation of hemochorial placental development.
| S-EPMC8052280 | biostudies-literature
Project description:Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here, we apply multi-omics to comprehensively define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Integrating the chromatin-bound proteome and histone modification data sets reveals differences in the relative abundance and activities of distinct chromatin modules, identifying a strong enrichment of Polycomb Repressive Complex 2 (PRC2)-associated H3K27me3 in naive pluripotent stem cell chromatin. Single-cell approaches and human blastoid models reveal that PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, and inhibiting PRC2 promotes trophoblast fate induction and cavity formation. Our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.
2022-05-06 | PXD028111 | Pride
Project description:The role of microRNAs (miRNA) in first cell fate choice of the preimplantation mouse embryo remains unresolved, as gene expression and knockout data are conflicting. This cell fate choice generates the extraembryonic lineage of the trophoblast and the embryonic lineage of the epiblast (inner cell mass). The trophoblast differentiates into polar and mural cells, where polar cells contribute to placental development and mural cells to the implantation process and Reichert’s membrane. The inner cell mass further differentiates into the epiblast and primitive endoderm. We used stem cell lines that can be derived from the trophoblast and epiblast lineages to address the role of miRNAs in early lineage cell fate specification and determination. Using embryonic stem cells (ESC) and trophoblast stem cells (TSC) as starting and ending states of cell development we identified a network of TSC expressed miRNAs that are enriched in ESC targets mRNA. We used constitutive and inducible expression of TSC enriched miRNAs in ESC and show that they can drive cell morphology and gene expression profiles similar to trophoblast. Additionally we show that this process required HDAC2 inhibition and is miRNA specific, as cardiac specific miR-1 could not induce trophoblast under these conditions. In contrast to embryo derived and Cdx2 induced trophoblast cells, miRNAs promote a mural TE like cell phenotype. Transplantation into preimplantation mouse embryos showed that miRNA-induced trophoblast preferentially contributes to the mural trophoblast in both the blastocyst and the Reichert’s membrane. Our data support a role for miRNAs and HDACs in the specification of the trophoblast and potentially the polar and mural cell types.
2017-03-01 | GSE79599 | GEO
Project description:Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with components of the Nuclear Receptor Corepressor Complex 1 and 2 (NCoR1 and NCoR2). Upon attenuation of Fgf signalling, unphosphorylated, nuclear Erf recruits the NCoR1/2 complex to key trophoblast genes, brings about their transcriptional silencing and facilitates differentiation and placental development.
2023-04-26 | PXD037892 | Pride
Project description:The Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate
| PRJNA818025 | ENA
Project description:Placental development relies on coordinated cell fate decisions governed by signalling inputs. However, little is known about how signalling cues are transformed into repressive lineage-specific transcriptional signatures. Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with the Nuclear Receptor Corepressor Complex 1 and 2 (NCoR1/2) and recruits it to key trophoblast genes. Genetic ablation of Erf or Tbl1x (a component of the NCoR1/2 complex) abrogates the Erf/NCoR1/2 interaction. This leads to mis-expression of Erf/NCor1/2 target genes resulting in a TSC differentiation defect. Mechanistically, Erf regulates expression of these genes by recruiting the NCoR1/2 complex to their enhancers and modulation of H3K27ac. Our findings uncover how the Fgf/Erf/NCoR1/2 repressive axis governs cell fate and placental development, providing a new paradigm for Fgf-mediated transcriptional control.
2023-04-26 | GSE199024 | GEO
Project description:Epigenetic histone trimethylation on lysine 9 (H3K9me3) represents a major molecular signal for genome stability and gene silencing conserved from worms to man. However, the functional role of the H3K9 trimethylases SUV39H1/2 in mammalian tissue homeostasis remains largely unknown. Here, we use a spontaneous dog model with monogenic inheritance of a recessive SUV39H2 loss-of-function variant and impaired differentiation in the epidermis, a self-renewing tissue fueled by stem and progenitor cell proliferation and differentiation. Our results demonstrate that SUV39H2 maintains the stem and progenitor cell pool by restricting fate conversion through H3K9me3 repressive marks on gene promoters encoding components of the Wnt/p63/adhesion axis. When SUV39H2 function is lost, repression is relieved, and enhanced Wnt activity causes progenitor cells to prematurely exit the cell cycle, a process mimicked by pharmacological Wnt activation in primary canine, human, and mouse keratinocytes. As a consequence, the stem cell growth potential of cultured SUV39H2-deficient canine keratinocytes is exhausted while epidermal differentiation and genome stability are compromised. Collectively, our data identify SUV39H2 and potentially also SUV39H1 as major gatekeepers in the delicate balance of progenitor fate conversion through H3K9me3 rate-limiting road blocks in basal layer keratinocytes.
| S-EPMC7898489 | biostudies-literature
Project description:To examine the molecular phenotype of Suv39h2-deficits during early neurodevelopment, transcriptome analysis in the E11.5 brain of Suv39h2-deficient mouse and wild-type littermates were performed. The Suv39h2 mutation was made using CRISPR/Cas9n-mediated genome editing
2023-12-30 | E-MTAB-10528 | biostudies-arrayexpress
Project description:Cell fate transitions involve rapid changes of gene expression patterns and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we used transcription-factor induced reprogramming of somatic cells into pluripotent cells to screen for novel regulators of cell fate change. We identified the RNA processing factor Nudt21, a component of the pre-mRNA cleavage and polyadenylation complex, as a potent barrier to reprogramming. Importantly, suppression of Nudt21 not only enhanced the generation of induced pluripotent stem cells but also facilitated the conversion of fibroblasts into trophoblast stem cells and delayed the differentiation of myeloid precursor cells into macrophages, suggesting a broader role for Nudt21 in restricting cell fate change. Polyadenylation site sequencing (PAS-seq) revealed that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency. While only a fraction of these transcripts changed expression at the protein level, this fraction was strongly enriched for chromatin regulators, including components of the PAF, polycomb, and trithorax complexes. Co-suppression analysis further suggests that these chromatin factors are largely responsible for Nudt21’s effect on reprogramming, providing a mechanistic basis for our observations. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of mammalian cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling.
2018-01-08 | PXD008078 | Pride