Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shed a light on mesenchymal chondrosarcoma tumorigenesis [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA802866 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17864456_1.fastq.gz | Fastqsanger.gz | |||
| SRR17864456_2.fastq.gz | Fastqsanger.gz | |||
| SRR17864457_1.fastq.gz | Fastqsanger.gz | |||
| SRR17864457_2.fastq.gz | Fastqsanger.gz | |||
| SRR17864458_1.fastq.gz | Fastqsanger.gz |
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Project description:Mesenchymal chondrosarcoma is a rare and often aggressive cancer that accounts for 2-10% of all chondrosarcomas. Genetically, this tumor is characterized by the recurrent HEY1-NCOA2 fusion. However, the oncogenic function of HEY1-NCOA2 fusion in mesenchymal chondrosarcoma remains to be elucidated. We stably transduced HEK293 as well as iPSC-derived mesenchymal stem cells (MSCs) with inducible- expression HEY1, NCOA2 and HEY1-NCOA2 construct, respectively. Using the stably transduced cell lines, we investigated the intracellular localization of HEY1-NCOA2 fusion protein and performed genome-wide chromatin Immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq) to identify HEY1-NCOA2-dependent transcriptional regulation. In this study, HEY1-NCOA2 fusion protein was found to be localized to the nucleus, like wild-type HEY1; and extreme similarity in genome-wide DNA-binding pattern between HEY1-NCOA2 and wild-type HEY1 was observed. By gene expression profiling, HEY1-NCOA2-expression (MSC-HN+), HEY1-expression (MSC-HEY1+) and NCOA2-expression (MSC-NCOA2+) iPSC-MSCs can be robustly separated, and the combined differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA) revealed that genes downregulated by HEY1 were positively enriched in MSC-HN+ versus control. Functional classification of HEY1-NCOA2 upregulated genes according to KEGG networks highlighted various pathways related to promoting cell proliferation in cancer, such as cell cycle pathway, Hedgehog and WNT signaling as well as PI3K-Akt signaling pathways. Indeed, MSC-HN+ cells displayed significantly accelerated proliferation and a significant increase in cell cycle transit when compared with control cells. In 3D spheroidal growth model, we also observed both accelerated cell proliferation and distinct morphological features of the MSC-HN+ cells in contrast to the control cells. Our data provide functional evidence that HEY1-NCOA2 fusion protein preferentially binds to DNA regions that are originally occupied by the wild-type HEY1 transcription factor, and the expression of some HEY1 target genes as well as their related pathways, that are normally repressed by HEY1, are activated in the presence of HEY1-NCOA2 fusion protein.
2022-04-08 | GSE196000 | GEO
Project description:Mesenchymal chondrosarcoma is a rare and often aggressive cancer that accounts for 2-10% of all chondrosarcomas. Genetically, this tumor is characterized by the recurrent HEY1-NCOA2 fusion. However, the oncogenic function of HEY1-NCOA2 fusion in mesenchymal chondrosarcoma remains to be elucidated. We stably transduced HEK293 as well as iPSC-derived mesenchymal stem cells (MSCs) with inducible- expression HEY1, NCOA2 and HEY1-NCOA2 construct, respectively. Using the stably transduced cell lines, we investigated the intracellular localization of HEY1-NCOA2 fusion protein and performed genome-wide chromatin Immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq) to identify HEY1-NCOA2-dependent transcriptional regulation. In this study, HEY1-NCOA2 fusion protein was found to be localized to the nucleus, like wild-type HEY1; and extreme similarity in genome-wide DNA-binding pattern between HEY1-NCOA2 and wild-type HEY1 was observed. By gene expression profiling, HEY1-NCOA2-expression (MSC-HN+), HEY1-expression (MSC-HEY1+) and NCOA2-expression (MSC-NCOA2+) iPSC-MSCs can be robustly separated, and the combined differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA) revealed that genes downregulated by HEY1 were positively enriched in MSC-HN+ versus control. Functional classification of HEY1-NCOA2 upregulated genes according to KEGG networks highlighted various pathways related to promoting cell proliferation in cancer, such as cell cycle pathway, Hedgehog and WNT signaling as well as PI3K-Akt signaling pathways. Indeed, MSC-HN+ cells displayed significantly accelerated proliferation and a significant increase in cell cycle transit when compared with control cells. In 3D spheroidal growth model, we also observed both accelerated cell proliferation and distinct morphological features of the MSC-HN+ cells in contrast to the control cells. Our data provide functional evidence that HEY1-NCOA2 fusion protein preferentially binds to DNA regions that are originally occupied by the wild-type HEY1 transcription factor, and the expression of some HEY1 target genes as well as their related pathways, that are normally repressed by HEY1, are activated in the presence of HEY1-NCOA2 fusion protein.
2022-04-08 | GSE196002 | GEO
Project description:Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shed a light on mesenchymal chondrosarcoma tumorigenesis
| PRJNA802864 | ENA
Project description:Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shed a light on mesenchymal chondrosarcoma tumorigenesis [ChIP-seq]
| PRJNA802858 | ENA
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program. We used microarrays to detail the global program of gene expression in mouse mesenchymal chondrosarcoma
2023-09-11 | GSE163291 | GEO
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program.
2023-09-11 | GSE163585 | GEO
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors (eSZ) followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression in eSZ cells successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation. Chromatin immunoprecipitation sequencing analyses indicated frequent association between HEY1-NCOA2-binding peaks and active enhancers. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. Whereas Runx2 knockout resulted in significant delay in tumor onset, aggressive growth of immature small round cells was induced. Treatment with the HDAC inhibitor panobinostat suppressed tumor growth both in vitro and in vivo, abrogating expression of genes downstream of HEY1-NCOA2 and Runx2. Thus, HEY1-NCOA2 expression induces malignant transformation by modulating the transcriptional program in chondrogenic differentiation.
2023-09-11 | GSE198662 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-04-08 | GSE196003 | GEO
Project description:Mesenchymal chondrosarcomas are fast-growing tumors that account for 2-10% of primary chondrosarcomas. Cytogenetic information is restricted to 12 cases that did not show a specific aberration pattern. Recently, two fusion genes were described in mesenchymal chondrosarcomas: a recurrent HEY1-NCOA2 found in tumors that had not been cytogenetically characterized and an IRF2BP2-CDX1 found in a tumor carrying a t(1;5)(q42;q32) translocation as the sole chromosomal abnormality. Here, we present the cytogenetic and molecular genetic analysis of a mesenchymal chondrosarcoma in which the patient had two histologically indistinguishable tumor lesions, one in the neck and one in the thigh. An abnormal clone with the G-banding karyotype 46,XX,add(6)(q23),add(8)(p23),del(10)(p11),+12,-15[6] was found in the neck tumor whereas a normal karyotype, 46,XX, was found in the tumor of the thigh. RT-PCR and Sanger sequencing showed that exon 4 of HEY1 was fused to exon 13 of NCOA2 in the sample from the thigh lesion; we did not have spare material to perform a similar analysis of the neck tumor. Examining the published karyotypes we observed numerical or structural aberrations of chromosome 8 in the majority of the karyotyped mesenchymal chondrosarcomas. Chromosome 8 was also structurally affected in the present study. The pathogenetic mechanisms behind this nonrandom involvement are unknown, but the presence on 8q of two genes, HEY1 and NCOA2, now known to be involved in mesenchymal chondrosarcoma tumorigenesis is, of course, suggestive.
| S-EPMC4067431 | biostudies-literature
Project description:Exparession profiling of ETV6-NCOA2 at different stages of disease dEmpty vectorelopment: CD34 cord blood cells transduced with ETV6-NCOA2-GFP or with empty vector-GFP, CD34 cord blood cells transduced with ETV6-NCOA2-NGFR or ETV6-NCOA2-NGFR + NOTCH1-L1601PdP-GFP and transplanted in NSGS mice, and ETV6-NCOA2 patient derived xenografts.
2022-05-16 | GSE161702 | GEO