Unique and redundant function of SOX2 and SOX17 in regulating the germ cell tumour fate
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130519 | GEO | 2019/09/28
REPOSITORIES: GEO
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Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells
A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation.
This model is described in the article:
In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R
BMC Genomics, 2009, 10:314
Abstract:
BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.
RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.
CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.
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2005-01-01 | MODEL1305010000 | BioModels
Project description:Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. The initial lesion is believed to be the relatively benign precursor lesion (ICGNU), from which either highly chemosensitive seminomas or the more aggressive non-seminomas develop. Previous analyses of selected genes have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. However, the genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours’ biology have not yet been established. Here genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data. This demonstrated that the seminoma cells exhibited very little aberrant DNA methylation while non-seminoma cells exhibited very high levels of DNA methylation. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested did indeed play a role in their silencing and many of these genes were also differentially expressed in primary tumours. Through this approach the genes silenced in the various GCT cell lines were identified. Conclusions: Several pluripotency-associated genes, never before implicated in this type of cancer, were identified as a major functional group of silenced genes. Silencing of these factors that normally suppress somatic differentiation might play an important role in the progression to non-seminoma formation.
2016-01-15 | GSE65027 | GEO
Project description:Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. The initial lesion is believed to be the relatively benign precursor lesion (ICGNU), from which either highly chemosensitive seminomas or the more aggressive non-seminomas develop. Previous analyses of selected genes have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. However, the genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours’ biology have not yet been established. Here genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data. This demonstrated that the seminoma cells exhibited very little aberrant DNA methylation while non-seminoma cells exhibited very high levels of DNA methylation. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested did indeed play a role in their silencing and many of these genes were also differentially expressed in primary tumours. Through this approach the genes silenced in the various GCT cell lines were identified. Conclusions: Several pluripotency-associated genes, never before implicated in this type of cancer, were identified as a major functional group of silenced genes. Silencing of these factors that normally suppress somatic differentiation might play an important role in the progression to non-seminoma formation.
2016-01-15 | GSE65026 | GEO
Project description:Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. The initial lesion is believed to be the relatively benign precursor lesion (ICGNU), from which either highly chemosensitive seminomas or the more aggressive non-seminomas develop. Previous analyses of selected genes have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. However, the genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumoursâ biology have not yet been established. Here genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data. This demonstrated that the seminoma cells exhibited very little aberrant DNA methylation while non-seminoma cells exhibited very high levels of DNA methylation. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested did indeed play a role in their silencing and many of these genes were also differentially expressed in primary tumours. Through this approach the genes silenced in the various GCT cell lines were identified. Conclusions: Several pluripotency-associated genes, never before implicated in this type of cancer, were identified as a major functional group of silenced genes. Silencing of these factors that normally suppress somatic differentiation might play an important role in the progression to non-seminoma formation. Genomic DNA and RNA was extracted from cell lines representing four subtypes of GCT. RNA was subjected to Affymetric expression array analysis while DNA was bisulfite treated and analysed using Illumina Infinium 450K arrays. Statistical approaches were used to correlate methylation and expression for each gene.
2016-01-15 | E-GEOD-65027 | biostudies-arrayexpress
Project description:Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. The initial lesion is believed to be the relatively benign precursor lesion (ICGNU), from which either highly chemosensitive seminomas or the more aggressive non-seminomas develop. Previous analyses of selected genes have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. However, the genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumoursâ biology have not yet been established. Here genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data. This demonstrated that the seminoma cells exhibited very little aberrant DNA methylation while non-seminoma cells exhibited very high levels of DNA methylation. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested did indeed play a role in their silencing and many of these genes were also differentially expressed in primary tumours. Through this approach the genes silenced in the various GCT cell lines were identified. Conclusions: Several pluripotency-associated genes, never before implicated in this type of cancer, were identified as a major functional group of silenced genes. Silencing of these factors that normally suppress somatic differentiation might play an important role in the progression to non-seminoma formation. Genomic DNA and RNA was extracted from cell lines representing four subtypes of GCT. RNA was subjected to Affymetric expression array analysis while DNA was bisulfite treated and analysed using Illumina Infinium 450K arrays. Statistical approaches were used to correlate methylation and expression for each gene.
2016-01-15 | E-GEOD-65026 | biostudies-arrayexpress
Project description:Type II germ cell tumors (GCTs) are the most common neoplasia in young men of age 14-45 years. It is generally accepted that GCTs arise from a common precursor lesion, called germ cell neoplasia in situ (GCNIS), eventually developing into seminomas or non-seminomas, such as (embryonal carcinomas, ECs). The latter stem-cell like EC can further differentiate into teratomas (TE), yolk-sac tumors (YST), or choriocarcinomas (CC). Even though cisplatin-based chemotherapy is an efficacious standard of care during the management of GCT patients, the development of cisplatin resistance remains a major obstacle. As such, the surrounding tumor microenvironment and its secreted factors could endorse the development of drug resistance. These stromal cells, including immune cells (e.g. macrophages, T-lymphocytes), endothelial cells, and fibroblasts, can influence tumor cells by promoting proliferative and anti-apoptotic signaling pathways. Vice versa, microenvironmental cells can be influenced by tumor cells as well. For the identification of secreted proteins, cell lysates and supernatants from seven human germ cell tumor cell lines (seminoma: TCam-2; embryonal carcinoma (EC): 2102EP, NCCIT; choriocarcinoma (CC): JAR, JEG-3), yolk-sac tumor (YST): GCT72; 1411H) and five human cell types from the microenvironment (fibroblasts: MPAF, HVHF2; M2 macrophages: THP-1-M2; T-lymphocytes: JURKAT; endothelial cells: HUVEC) have been evaluated using liquid chromatography coupled with mass spectrometry (LC-MS).
2022-10-13 | PXD031329 | Pride
Project description:We show here by using genome-wide ChIP-sequencing that lineage segregation involves multiple Sox/Oct partnership. In undifferentiated ES cells Oct4 interacts with Sox2 and both TFs bind on the 'canonical' motif, whereas in cells commited to PrE lineage Oct4 switches from Sox2 to Sox17 interaction and this complex bind to a unique "compressed" motif. ChIP-sequencing has been done for Sox2, Sox17 and Oct4 in the pluripotent context or PrE context
2013-04-23 | E-GEOD-43275 | biostudies-arrayexpress
Project description:Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4defSox2). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance.
2019-06-18 | GSE119396 | GEO
Project description:Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4defSox2). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance.
2019-06-18 | GSE103979 | GEO
Project description:Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4defSox2). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance.
2019-06-18 | GSE103980 | GEO