Epigenetic regulation during cancer transitions across 11 tumour types.
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ABSTRACT:
PROVIDER: PRJNA1005321 | ENA |
REPOSITORIES: ENA
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Project description:Chromatin accessibility plays an essential role in regulating gene expression and cellular identity, and its alterations have been implicated in driving oncogenic processes such as cancer initiation, progression, and metastasis1–4. While genetic aspects of cancer transitions have been explored, the role of epigenetic drivers remains less understood. To investigate the influence of chromatin architecture on cancer transitions, we generated an atlas of single-nucleus chromatin accessibility data (snATAC-seq) from 225 samples and matched single-cell/single-nucleus RNA expression (sc/snRNA-seq) from 206 samples across 11 cancer types. Analyzing over 1 million cells, we identified pan-cancer epigenetic drivers and transcriptional programs associated with transitions (regulatory regions of ABCC1, VEGFA, and GATA6, KLF6 and FOX-family TFs), as well as cancer type specific programs (regulatory regions of FGF19, ASAP2, EN1 and PBX3 TF). Differentially-accessible chromatin regions pinpointed genes and enriched pathways associated with major cancer transitions. For example, TP53, hypoxia, and TNFA signaling were linked to cancer initiation, while estrogen response, epithelial-mesenchymal transition (EMT), myogenesis, and apical junction were linked to metastatic transition. We also observed correlations between regulatory regions and genetic drivers across cancer types, suggesting their cooperation in cancer transition programs. This atlas furnishes a valuable resource for further investigation of the role of epigenetic programs in cancer initiation, progression, and metastasis.
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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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