Intrinsic epigenetic state of primary osteosarcoma drives metastasis [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA983858 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24921900_1.fastq.gz | Fastqsanger.gz | |||
| SRR24921900_2.fastq.gz | Fastqsanger.gz | |||
| SRR24921901_1.fastq.gz | Fastqsanger.gz | |||
| SRR24921901_2.fastq.gz | Fastqsanger.gz | |||
| SRR24921902_1.fastq.gz | Fastqsanger.gz |
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Project description:Intrinsic epigenetic state of primary osteosarcoma drives metastasis.
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Project description:Osteosarcoma (OS) is a primary malignant bone tumor commonly affecting children, adolescents, and young adults with a potential to metastasize to distal sites, most commonly lung. Here, we mapped the active chromatin landscapes of OS patients with varying extent of disease. We integrated histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) of OS tumors from four different diseased states to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary tumors that undergo metastasis (primary mets) have a distinct enhancer landscape compared to primary tumors that remain localized (localized) during the course of disease. The difference in chromatin activity shapes the transcriptional profile of OS patients. Some of the genes like PPP1R1B, PREX1 and IGF2BP1 whose role in OS pathogenesis and metastasis remains poorly understood, exhibit increased enhancer activity in primary mets along with higher RNA levels. Genome-wide loss-of-function screens also reveal these genes to be as selective dependencies in bone sarcomas, making them promising candidates for further investigation. Overall, differential chromatin activity in primary mets occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and migration process suggestive of their role in facilitating OS metastasis. Thus, this data demonstrates that metastatic potential is intrinsically present in primary mets OS much before the occurrence of metastasis and when the cells are presented with favorable conditions to migrate and colonize at a distant site, they under undergo metastasis.
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Project description:Osteosarcoma (OS) is a primary malignant bone tumor commonly affecting children, adolescents, and young adults with a potential to metastasize to distal sites, most commonly lung. Here, we mapped the active chromatin landscapes of OS patients with varying extent of disease. We integrated histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) of OS tumors from four different diseased states to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary tumors that undergo metastasis (primary mets) have a distinct enhancer landscape compared to primary tumors that remain localized (localized) during the course of disease. The difference in chromatin activity shapes the transcriptional profile of OS patients. Some of the genes like PPP1R1B, PREX1 and IGF2BP1 whose role in OS pathogenesis and metastasis remains poorly understood, exhibit increased enhancer activity in primary mets along with higher RNA levels. Genome-wide loss-of-function screens also reveal these genes to be as selective dependencies in bone sarcomas, making them promising candidates for further investigation. Overall, differential chromatin activity in primary mets occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and migration process suggestive of their role in facilitating OS metastasis. Thus, this data demonstrates that metastatic potential is intrinsically present in primary mets OS much before the occurrence of metastasis and when the cells are presented with favorable conditions to migrate and colonize at a distant site, they under undergo metastasis.
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Project description:Osteosarcoma (OS) is a primary malignant bone tumor commonly affecting children, adolescents, and young adults with a potential to metastasize to distal sites, most commonly lung. Here, we mapped the active chromatin landscapes of OS patients with varying extent of disease. We integrated histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) of OS tumors from four different diseased states to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary tumors that undergo metastasis (primary mets) have a distinct enhancer landscape compared to primary tumors that remain localized (localized) during the course of disease. The difference in chromatin activity shapes the transcriptional profile of OS patients. Some of the genes like PPP1R1B, PREX1 and IGF2BP1 whose role in OS pathogenesis and metastasis remains poorly understood, exhibit increased enhancer activity in primary mets along with higher RNA levels. Genome-wide loss-of-function screens also reveal these genes to be as selective dependencies in bone sarcomas, making them promising candidates for further investigation. Overall, differential chromatin activity in primary mets occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and migration process suggestive of their role in facilitating OS metastasis. Thus, this data demonstrates that metastatic potential is intrinsically present in primary mets OS much before the occurrence of metastasis and when the cells are presented with favorable conditions to migrate and colonize at a distant site, they under undergo metastasis.
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Project description:Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize to distal sites, most commonly the lung. Insights into defining molecular features contributing to metastatic potential are lacking. We have mapped the active chromatin landscapes of OS tumors by integrating histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to primary tumors from patients without metastatic disease (localized). The difference in chromatin activity shapes the transcriptional profile of OS. We identified novel candidate genes involved in OS pathogenesis and metastasis, including PPP1R1B, PREX1 and IGF2BP1, which exhibit increased chromatin activity in primary met along with higher transcript levels. Overall, differential chromatin activity in primary met occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Furthermore, chromatin profiling of tumors from metastatic lung lesions noted increases in chromatin activity in genes involved in cell migration and key intracellular signaling cascades, including the Wnt pathway. Thus, this data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors and the cellular chromatin profiles further adapt to allow for successful dissemination, migration, and colonization at the distal metastatic site.
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Project description:Aberrations in the Hedgehog (Hh) pathway are known to related to several malignancies. However, little is known about the function of GLI2, a transcription factor in the Hh pathway, in osteosarcoma. Osteosarcoma is the most frequent primary bone sarcoma in children and adolescents. Despite survival rates of osteosarcoma patients have increased, the prognosis of patients with metastasis remains poor. Therefore, the development of novel therapeutic strategies for osteosarcoma patients is development of novel therapeutic strategies for osteosarcoma patients is urgently needed. Aberrations in the Hedgehog (Hh) pathway are known to related to several malignancies. However, little is known about the function of GLI2, a transcription factor in the Hh pathway, in osteosarcoma. Our findings revealed that GLI2 was overexpressed in osteosarcoma tissues. Additionally, GLI2 is involved in the metastasis of osteosarcoma cells through the regulation of ribosomal protein S3 expression. Furthermore, we showed that arsenic trioxide (ATO) suppressed the invasion and lung metastasis of osteosarcoma cells by the inhibition of GLI transcription. Consequently, these finding reveal a novel function of GLI2 in the metastasis of osteosarcoma and that ATO may be a new therapeutic agentay be a new therapeutic agent. We revealed that a novel function of GLI2 in the metastasis of osteosarcoma and that ATO may be a new therapeutic agent for preventing osteosarcoma metastasis. Negative siRNA(U-2OS) and GLI2 siRNA(U-2OS)
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