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Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid [RNA-seq]

ABSTRACT: Retinoic acid (RA) is a standard-of-care neuroblastoma drug thought to act primarily via differentiation. However, this has never been conclusively demonstrated in vivo. Curiously, RA has little effect shrinking primary human tumors when applied in upfront treatment but can eliminate neuroblastoma cells from the bone marrow during consolidation therapy—a discrepancy that has never been explained. To investigate this, we treated a large cohort of neuroblastoma cell lines with RA and observed that the most RA-sensitive cells tended to undergo apoptosis or senescence, rather than differentiation. We conducted genome-wide CRISPR knockout screens under RA treatment, which identified BMP signaling as controlling the apoptosis/senescence vs differentiation cell fate decision and RA’s overall potency. We then conducted integrative analysis of high throughput ChIP-seq and RNA-seq data, which indicates that downstream BMP and RA transcription factors cooperate to determine cell fate, following exposure to RA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253785 | GEO | 2024/05/31

REPOSITORIES: GEO

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Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid [ChIP-seq]

Project description:Retinoic acid (RA) is a standard-of-care neuroblastoma drug thought to act primarily via differentiation. However, this has never been conclusively demonstrated in vivo. Curiously, RA has little effect shrinking primary human tumors when applied in upfront treatment but can eliminate neuroblastoma cells from the bone marrow during consolidation therapy—a discrepancy that has never been explained. To investigate this, we treated a large cohort of neuroblastoma cell lines with RA and observed that the most RA-sensitive cells tended to undergo apoptosis or senescence, rather than differentiation. We conducted genome-wide CRISPR knockout screens under RA treatment, which identified BMP signaling as controlling the apoptosis/senescence vs differentiation cell fate decision and RA’s overall potency. We then conducted integrative analysis of high throughput ChIP-seq and RNA-seq data, which indicates that downstream BMP and RA transcription factors cooperate to determine cell fate, following exposure to RA.

2024-05-31 | GSE253786 | GEO

Netrin1 patterns the dorsal spinal cord through modulation of Bmp signaling

Project description:We directed mESCs towards the dorsal sensory interneurons (dIs) using RA-/+ BMP4 and tested the effects of an axon guidance molecule netrin1 on dI differentiation in vitro. Using bulk-RNA seq analysis, we investiagted when the addition of netrin 1 will affect the transcriptome of differentiating dIs. For this analysis, we used three timewindows (conditions 1-3) for netrin addition (1) condition 1 netrin 1 was added together with RA+BMP4 at day 4, and RNA seq was conducted at day 5, (2) netrin1 was added after the RA+BMP4 mediated patterning at day 5 and RNA seq was conducted at day 6, and (3) netrin1 was added for the extended duration between day 5-day9 to investigate the netrin1 effects throughout the dI differentiation and RNA seq was conducted at day 9. Through this analysis we identified that netrin1 downregulate BMP signaling pathway, possibly through modlulating the mRNA processing of key mediator of BMP signaling such as Id genes and BMP signaling inhibitor Smad7 and affect dI differentiation. This is the first report to show that netrin1 regulate dI fate specification in the dorsal spinal cord.

2024-04-23 | GSE246903 | GEO

Next generation sequencing facilitates lineage identity of RA-induced and RA/CHIR-induced ESCs

Project description:To uncover the mechanism that Wnt signaling modulates RA-induced ESC differentiation, we conducted time course RNA-seq analysis during the differentiation. Transcriptome profiles of RA-induced and RA/CHIR-induced ESC differentiation were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. The RNA-seq data revealed a significant decrease in mesoderm (one of the major source of vascular SMCs) markers and increase in PrE markers in CHIR treated samples, while other lineage markers showed no significant expression, implying a diverging to PrE fate by Wnt activation. Subsequent hierarchical clustering analysis also showed that the gene expression profiles of cells derived from RA induction alone clustered with adult SMCs, while cells derived from RA/CHIR induction gradually clustered to XEN cells with differentiation and was very close to XEN cells at day 16, suggesting that RA/CHIR-induced ESCs differentiated into PrE lineage. This study provided new insights into the importance of RA/Wnt crosstalk in the lineage differentiation of ESCs.

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ZGLP1 is a determinant for the oogenic fate in mice (RNA-seq)

Project description:Mammalian sexual reproduction relies on the dichotomy of male and female germ cell development. However, the underlying mechanisms remain unclear. Here, we show that ZGLP1, a conserved transcriptional regulator with GATA-like zinc fingers, determines the oogenic fate in mice. ZGLP1 acts downstream of bone morphogenetic protein (BMP), but not retinoic acid (RA), and is essential for the oogenic program and meiotic entry. ZGLP1 overexpression induces differentiation of in vitro primordial germ cell-like cells (PGCLCs) into fetal oocytes by activating the oogenic programs repressed by Polycomb activities, whereas RA signaling contributes to the oogenic program maturation and PGC program repression. Our findings elucidate the mechanism for mammalian oogenic fate determination, providing a foundation for promoting in vitro gametogenesis and reproductive medicine.

2020-02-21 | GSE124261 | GEO

ZGLP1 is a determinant for the oogenic fate in mice (ChIP-seq)

2020-02-21 | GSE124260 | GEO

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression [RNA-Seq]

Project description:Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

2017-06-28 | GSE100568 | GEO

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression [array]

Project description:Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNAdemethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

2017-08-23 | GSE102994 | GEO

Mastermind-like 3 controls proliferation and differentiation in neuroblastoma (RNA-seq)

Project description:Neuroblastoma cell lines can differentiate upon retinoic acid (RA) treatment, a finding that provided the basis for the clinical use of RA to treat neuroblastoma. However, resistance to RA is often observed, which limits its clinical utility. Using a gain-of-function genetic screen we identify the transcriptional coactivator Mastermind-like 3 (MAML3) as a gene whose ectopic expression confers resistance to RA. We find that MAML3 expression leads to loss of activation of a subset of RA target genes, which hampers RA-induced differentiation. The regulatory DNA elements of this subset of RA target genes show overlap in binding of MAML3 and the retinoic acid receptor, suggesting a role for MAML3 in the regulation of these genes. In addition, MAML3 has RA independent functions, including the activation of IGF1R and downstream AKT signaling via upregulation of IGF2, resulting in increased proliferation. Our results indicate an important role for MAML3 in differentiation and proliferation of neuroblastomas.

2016-01-31 | GSE69121 | GEO

Mastermind-like 3 controls proliferation and differentiation in neuroblastoma (ChIP-seq)

2016-01-31 | GSE69119 | GEO

Lamin A/C is required for SHSY5Y neuroblastoma cell differentiation and its expression is linked to a less malignant phenotype.

Project description:The main scientific objective of the project was to investigate whether Lamin A/C could be involved in neuroblastoma differentiation. Moreover, taking into account the significance of differentiation stage in the neuroblastoma tumor progression we have also studied a possible role of Lamin A/C in the tumorigenesis of this neuronal cancer. As differentiating stimulus we used the all-trans retinoic acid (RA), the most effective compound which has been shown to induce differentiation in neuroblastoma cells. To get insight into the impairment of cell differentiation produced by the LMNA (Lamin A/C) silencing in SHSY5Y cells, we compared the gene expression profile of control and silenced cells both in Retinoic Acid treated and untreated samples, using the one-color Agilent microarray platform. Four condition experiment: cells infected with a mock vector (Mock cells), treated and untreated with retinoic acid (RA); cells infected with a silencing vector for LMNA (LMNA-KD cells), treated and untreated with retinoic acid.

2013-07-11 | E-GEOD-30677 | biostudies-arrayexpress

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