Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype
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ABSTRACT:
PROVIDER: EGAS00001003953 | EGA |
REPOSITORIES: EGA
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
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Project description:BRD4 is a key regulatory factor in multiple cancers and cellular stress responses with pleotropic functions. BRD4 regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities, respectively. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that in response to a broad range of stimuli, this switch is mediated by the JNK kinase which directly interacts with BRD4. JNK specifically phosphorylates human BRD4 at Ser1117, Thr1186 and Thr1212, triggering transient BRD4 release from chromatin. JNK phosphorylation of BRD4 halts its HAT-mediated chromatin regulation and activates its transcription-enhancing kinase function. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. BRD4 release from chromatin augments its interaction with and phosphorylation of key transcriptional regulators RNA Pol II, PTEFb and c-MYC. The PP4 phosphatase dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which promotes its interaction with RNA Pol II at transcriptionally active sites. Accordingly, JNK-mediated release of BRD4 from chromatin leads to significantly elevated transcription of BRD4-regulated immune and inflammatory response genes through enhanced BRD4-Pol II interaction at the promoters of these genes. JNK phosphorylation of BRD4 occurs during T-cell activation and is required for epithelial to mesenchymal transition (EMT) in prostate cancer cells. These findings thus characterize a novel mechanism that triggers the transition of BRD4 from a chromatin regulator to transcriptional activator during stress/immune/inflammatory responses and EMT.
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