Epigenetic reprogramming shapes the cellular landscape of schwannoma, DNA Methylation
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PROVIDER: PRJNA917427 | ENA |
REPOSITORIES: ENA
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Project description:Cell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2–5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.
2023-04-18 | PXD014798 | Pride
Project description:Cell state evolution underlies tumor development and response to therapy, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation. Schwannomas can oscillate in size for many years after radiotherapy, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 methylation based molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.
2023-01-02 | GSE222042 | GEO
Project description:Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.
| S-EPMC10786948 | biostudies-literature
Project description:Epigenome analysis of schwannoma tumor samples
2016-10-10 | GSE79009 | GEO
Project description:Genome-wide profiling establishes that human cytomegalovirus (HCMV) exerts an extensive, unforeseen level of specific control over which cellular mRNAs are recruited to or excluded from polyribosomes. The landscape of translationally-regulated host mRNAs regulates HCMV replication. The HCMV imposed translational signature shares similarities with cancer cells Two biological replicate experiments were performed profiling total and polysomal mRNAs from i) HCMV-infected vs mock-infected cells and ii) uninfected cells transduced with a lentivirus expressing doxycyclin (dox)-inducible HCMV UL38 +/- dox. Analysis of translationally-controlled host genes in HCMV-infected cell and cells expressing the HCMV UL38 gene product
2013-11-01 | E-GEOD-50938 | biostudies-arrayexpress
Project description:To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naive and differentiated cells in the presence and absence of the DNA methylation machinery.
2024-07-16 | GSE242201 | GEO
Project description:Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Chromatin-modifying enzymes are dependent on metabolic intermediates for chromatin remodeling, linking nutrient availability and cellular metabolism to the cellular epigenetic landscape. Here we identify methionine as a key nutrient affecting T cell epigenetic reprogramming in CD4+ T helper (Th) cells. Using metabolomic approaches, we showed that methionine is rapidly taken up by activated T cells and then serves as the major substrate for the biosynthesis of S-adenosyl-L-methionine (SAM), the universal methyl donor for cellular methyltransferases. Conversely, methionine restriction (MR) depletes intracellular SAM pools, reduces global histone H3K4 methylation (H3K4me3) in T cells, and reduces H3K4me3 levels at the promoter regions of key genes involved in CD4+ Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset. Overall our data identify methionine as a key nutritional factor that shapes T cell proliferation, differentiation, and function in part through regulation of histone methylation in T cells.
2020-02-03 | GSE143321 | GEO
Project description:Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Chromatin-modifying enzymes are dependent on metabolic intermediates for chromatin remodeling, linking nutrient availability and cellular metabolism to the cellular epigenetic landscape. Here we identify methionine as a key nutrient affecting T cell epigenetic reprogramming in CD4+ T helper (Th) cells. Using metabolomic approaches, we showed that methionine is rapidly taken up by activated T cells and then serves as the major substrate for the biosynthesis of S-adenosyl-L-methionine (SAM), the universal methyl donor for cellular methyltransferases. Conversely, methionine restriction (MR) depletes intracellular SAM pools, reduces global histone H3K4 methylation (H3K4me3) in T cells, and reduces H3K4me3 levels at the promoter regions of key genes involved in CD4+ Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset. Overall our data identify methionine as a key nutritional factor that shapes T cell proliferation, differentiation, and function in part through regulation of histone methylation in T cells.
2020-02-03 | GSE143320 | GEO
Project description:Individual induced pluripotent stem cells (iPSCs) show considerable phenotypic heterogeneity, but the reasons for this are not fully understood. Comprehensively analysing the mitochondrial genome (mtDNA) in 146 iPSC and fibroblast lines from 151 donors, we show that most age-related fibroblast mtDNA mutations are lost during reprogramming. However, iPSC-specific mutations are seen in 76.6% (108/141) of iPSC lines at a mutation rate of 8.62 × 10-5/base pair. The mutations observed in iPSC lines affect a higher proportion of mtDNA molecules, favouring non-synonymous protein-coding and tRNA variants, including known disease-causing mutations. Analysing 11,538 single cells shows stable heteroplasmy in sub-clones derived from the original donor during differentiation, with mtDNA variants influencing the expression of key genes involved in mitochondrial metabolism and epidermal cell differentiation. Thus, the dynamic mtDNA landscape contributes to the heterogeneity of human iPSCs and should be considered when using reprogrammed cells experimentally or as a therapy.
| S-EPMC8413449 | biostudies-literature