BMP4 Signaling Plays a Critical Roles in Self-renewal of R2i Mouse Embryonic Stem Cells
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ABSTRACT:
PROVIDER: PRJNA729061 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14514868_1.fastq.gz | Fastqsanger.gz | |||
| SRR14514868_2.fastq.gz | Fastqsanger.gz | |||
| SRR14514869_1.fastq.gz | Fastqsanger.gz | |||
| SRR14514869_2.fastq.gz | Fastqsanger.gz | |||
| SRR14514870_1.fastq.gz | Fastqsanger.gz |
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Project description:Mouse embryonic stem cells (mESCs) can be maintained in a pluripotent state under R2i culture conditions that inhibit the TGF-β and ERK signaling pathways. BMP4 is another member of the TGF-β family that plays a crucial role in maintaining the pluripotency state of mESCs. It has been reported that inhibition of BMP4 caused the death of R2i-grown cells. In this study, we used the loss-of-function approach to investigate the role of BMP4 signaling in mESC self-renewal. Inhibition of this pathway with Noggin and dorsomorphin, two bone morphogenetic protein (BMP) antagonists, elicited a quick death of the R2i-grown cells. We showed that the canonical pathway of BMP4 (BMP/SMAD) was dispensable for self-renewal and maintaining pluripotency of these cells. Transcriptome analysis of the BMPi-treated cells revealed that the p53 signaling and two adhesion (AD) and apoptotic mitochondrial change (MT) pathways could be involved in the cell death of the BMPi-treated cells. According to our results, inhibition of BMP4 signaling caused a decrease in cell adhesion and ECM detachment, which triggered anoikis in the R2i-grown cells. Altogether, these findings demonstrate that endogenous BMP signaling is required for survival of mESCs under the R2i condition.
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Project description:Trophoblast stem cells (TSCs) are derived from the trophoectoderm of a blastocyst and can maintain self-renewal in vitro. Meanwhile, essential insights into the molecular mechanisms controlling placental developmental could be gained by using TSCs that can differentiate into the various placental trophoblast cell types in vitro. Esrrb is a transcription factor with pivotal roles in maintaining TSCs’ self-renewal, but the exact transcriptional networks that Esrrb involved in TSCs are largely unknown. In the present study, we elucidated the function of Esrrb during TSC self-renewal and differentiation. We demonstrate that precise levels of Essrb are critical for TSCs stemness maintenance and normal trophoblast differentiation, as Esrrb depletion results in down-regulation of the key TSC-specific transcription factors, consequently causing TSCs differentiation and forced expression of Esrrb can partially block TSCs differentiation in the absence of FGF4. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4 and BMP4. Furthermore, we investigate the role of Esrrb in reprogramming of mouse embryonic fibroblasts (MEFs) to induced TSCs (iTSCs). We show that Esrrb can facilitate the conversion of iTSCs from MEFs. Moreover, Esrrb can substitute for Eomes during this conversion process. Our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSCs self-renewal and iTSCs reprogramming.
2019-10-06 | GSE104695 | GEO
Project description:Trophoblast stem cells (TSCs) are derived from the trophoectoderm of a blastocyst and can maintain self-renewal in vitro. Meanwhile, essential insights into the molecular mechanisms controlling placental developmental could be gained by using TSCs that can differentiate into the various placental trophoblast cell types in vitro. Esrrb is a transcription factor with pivotal roles in maintaining TSCs’ self-renewal, but the exact transcriptional networks that Esrrb involved in TSCs are largely unknown. In the present study, we elucidated the function of Esrrb during TSC self-renewal and differentiation. We demonstrate that precise levels of Essrb are critical for TSCs stemness maintenance and normal trophoblast differentiation, as Esrrb depletion results in down-regulation of the key TSC-specific transcription factors, consequently causing TSCs differentiation and forced expression of Esrrb can partially block TSCs differentiation in the absence of FGF4. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4 and BMP4. Furthermore, we investigate the role of Esrrb in reprogramming of mouse embryonic fibroblasts (MEFs) to induced TSCs (iTSCs). We show that Esrrb can facilitate the conversion of iTSCs from MEFs. Moreover, Esrrb can substitute for Eomes during this conversion process. Our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSCs self-renewal and iTSCs reprogramming.
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Project description:The Ets2 transcription factor is essential for the development of the mouse placenta and for generating signals for embryonic mesoderm and axis formation. Using a conditional targeted Ets2 allele, we show that Ets2 is essential for trophoblast stem (TS) cells self renewal. Inactivation of Ets2 results in slower growth, increased expression of a subset of differentiation associated genes and decreased expression of several genes implicated in TS self renewal. Among the direct TS targets of Ets2 is Cdx2, a key master regulator of TS cell state. In addition other Ets2 responsive genes include Pace4, Errb, Socs2 and Bmp4. Thus Ets2 contributes to the regulation of multiple genes important for maintaining the undifferentiated state of TS cells and as candidate signals for embryonic development. Keywords: cell type comparison
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Project description:Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and often associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators, we have analyzed the protein secretome of human endothelial cells in the presence of sEng. We find that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased levels of BMP4 transcripts in lungs and increased circulating BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appears 18 days after mating, precisely coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 are positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the pathobiology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
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Project description:Embryonic stem cell (ESC) self-renewal and pluripotency is controlled by the coordinated action of transcription factors and chromatin regulators. Compared to the pluripotency transcription factors, the function of the chromatin regulators, especially the ATP-dependent chromatin remodelers, remains poorly understood in ESCs. Here, we show that INO80, a SWI/SNF family chromatin remodeling complex, is essential for ESC self-renewal, pluripotency, somatic cell reprogramming, and embryonic development. Ino80, the ATPase of the complex, forms an auto-regulatory loop with the ESC master transcription factors Oct4, Nanog, and Sox2. More importantly, it co-occupies the enhancer regions of most key pluripotency genes with the master transcription factors, and positively regulates their expression by maintaining an open chromatin structure. Our data suggests that INO80 is an integral component of the pluripotency transcription network, and plays a critical role in both the maintenance and establishment of pluripotency Identification of Ino80 localization in mouse embryonic stem cells
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