Genome-wide maps of DNA methylation and gene expression for multiple regions within a breast tumor [RRBS]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124027 | GEO | 2020/01/01
REPOSITORIES: GEO
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Project description:As the differentiation state of the cells is affected by epigenetic modification regulation, the abnormal epigenetic modification is an important factor leading to the intratumoral heterogeneity. To further understand of the intratumoral epigenetic heterogeneity, we performed Reduced Representation Bisulfite Sequencing and RNA sequencing for multiple regions within a breast tumor and exhibited the epigenetic maps of different regions. We detected intratumoral heterogeneity-related molecular features and further explored the correlation between tumor heterogeneity and tumor hypoxic microenvironment.
2020-01-01 | GSE124030 | GEO
Project description:Human tumors are comprised of heterogeneous cell populations that display diverse molecular and phenotypic features. To examine the extent to which epigenetic differences contribute to intratumoral cellular heterogeneity, we have developed a high-throughput method, termed MAPit-patch. The method uses multiplexed amplification of targeted sequences from sub-microgram input quantities of genomic DNA followed by next generation bisulfite sequencing. This provides highly scalable and simultaneous mapping of chromatin accessibility and DNA methylation on single molecules at high resolution. Long sequencing reads from targeted regions maintains the structural integrity of epigenetic information and provides substantial depth of coverage, detecting for the first time minority subpopulations of epigenetic configurations formerly obscured by existing genome-wide and population-ensemble methodologies. Analyzing a cohort of 71 promoters of genes with exons commonly mutated in cancer, MAPit-patch uncovered several differentially accessible and methylated promoters that are associated with altered gene expression between neural stem cell (NSC) and glioblastoma (GBM) cell populations. Additionally, substantial epigenetic heterogeneity was observed across the sequenced molecules at individual promoters, indicating the presence of epigenetically distinct cellular subpopulations. This study includes 4 samples, NSC probed with 100U M.CviPI and 0U control; GBM probed with 100U M.CviPI and 0U control.
2013-10-03 | E-GEOD-50047 | biostudies-arrayexpress
Project description:We performed reduced representation bisulfite seqeuncing (RRBS) and ChIP-seq of histone modification marks on three Ewing sarcoma tumor samples, and we quantified epigenetic heterogeneity on three levels. First, we identified a Ewing sarcoma specific hypomethylation signature at EWS-FLI1 regulated enhancers, showing that epigenetic enhancer reprogramming is a defining feature of Ewing sarcoma. Second, inter-individual DNA methylation differences in Ewing sarcoma samples identified a continuous disease spectrum with two dimensions: the strength of the EWS-FLI1 regulatory signature and the balance of mesenchymal versus stem cell regulatory signatures. Third, we observed substantial epigenetic heterogeneity within individual tumors. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma, highlighting its importance as a source of variability for genetically homogeneous tumors.
2017-01-30 | GSE89026 | GEO
Project description:Despite rapid progress in characterizing transcription factor-driven reprogramming of somatic cells to an induced pluripotent stem (iPS) cell state, many mechanistic questions still remain. To gain insight into the earliest events in the reprogramming process, we systematically analyzed the transcriptional and epigenetic changes that occur during early factor induction after discrete numbers of divisions. We observed rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more than a thousand loci including large subsets of pluripotency or developmentally related gene promoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remained largely unchanged except for focused depletion specifically at positions where H3K4 methylation is gained. These chromatin regulatory events precede transcriptional changes within the corresponding loci. Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopic reprogramming factors that clarify the temporal order through which somatic identity is reset during reprogramming. Genome-scale DNA methylation was measured by reduced representation bisulfite sequencing (RRBS) during the initial phase in the reprogramming of mouse embryonic fibroblasts.
2011-01-03 | E-GEOD-26098 | biostudies-arrayexpress
Project description:Composed of negative feedback loops, circadian oscillations are thought to be noise-resistant. Yet, individual cells in culture are remarkably heterogenous, oscillating independently and with different period lengths. To assess whether differential methylation contributes to heritable heterogeneity of circadian periods, we used reduced representation bisulfite sequencing (RRBS) to explore DNA methylation profiles and their correlation with the transcriptome in the 10 clonal cell lines. To investigate the mechanisms underlying this heterogeneity, we generated and characterized hundreds of clonal cell lines from the same parent culture. By comparing clonal lines with different circadian periods, we identified a group of differentially methylated regions (DMRs).
2020-06-09 | GSE132665 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+ macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC , ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+ cells associated with a reactive phenotype and reduced CD8+ T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+ T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.
2023-12-31 | GSE245941 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+ macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC , ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+ cells associated with a reactive phenotype and reduced CD8+ T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+ T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.
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Project description:The integration of DNA methylation and transcriptional state within single cells is of broad interest. Several single-cell dual- and multi-omics approaches have been reported recently that will enable further investigation into cellular heterogeneity including the discovery and in depth study of rare cell populations. Such analyses will continue to provide important mechanistic insights into the regulatory consequences of epigenetic modifications. Last year we reported a new method for profiling the DNA methylome and transcriptome from the same single cell. Here we present details of the protocol and provide guidance on its utility. Our Smart-RRBS protocol entails physically separating mRNA and genomic DNA and combines Smart-Seq2 and Reduced Representation Bisulfite Sequencing (RRBS). It generates paired epigenetic promoter and RNA-expression measurements for a substantial fraction (approximately one-fourth) of protein-coding genes in a typical single cell. It also works for micro-dissected tissue samples comprising hundreds of cells. The protocol, excluding sequencing, takes ~3 days to process up to 192 samples manually
2021-04-15 | GSE157113 | GEO
Project description:The integration of DNA methylation and transcriptional state within single cells is of broad interest. Several single-cell dual- and multi-omics approaches have been reported recently that will enable further investigation into cellular heterogeneity including the discovery and in depth study of rare cell populations. Such analyses will continue to provide important mechanistic insights into the regulatory consequences of epigenetic modifications. Last year we reported a new method for profiling the DNA methylome and transcriptome from the same single cell. Here we present details of the protocol and provide guidance on its utility. Our Smart-RRBS protocol entails physically separating mRNA and genomic DNA and combines Smart-Seq2 and Reduced Representation Bisulfite Sequencing (RRBS). It generates paired epigenetic promoter and RNA-expression measurements for a substantial fraction (approximately one-fourth) of protein-coding genes in a typical single cell. It also works for micro-dissected tissue samples comprising hundreds of cells. The protocol, excluding sequencing, takes ~3 days to process up to 192 samples manually
2021-04-15 | GSE157114 | GEO
Project description:Human tumors are comprised of heterogeneous cell populations that display diverse molecular and phenotypic features. To examine the extent to which epigenetic differences contribute to intratumoral cellular heterogeneity, we have developed a high-throughput method, termed MAPit-patch. The method uses multiplexed amplification of targeted sequences from sub-microgram input quantities of genomic DNA followed by next generation bisulfite sequencing. This provides highly scalable and simultaneous mapping of chromatin accessibility and DNA methylation on single molecules at high resolution. Long sequencing reads from targeted regions maintains the structural integrity of epigenetic information and provides substantial depth of coverage, detecting for the first time minority subpopulations of epigenetic configurations formerly obscured by existing genome-wide and population-ensemble methodologies. Analyzing a cohort of 71 promoters of genes with exons commonly mutated in cancer, MAPit-patch uncovered several differentially accessible and methylated promoters that are associated with altered gene expression between neural stem cell (NSC) and glioblastoma (GBM) cell populations. Additionally, substantial epigenetic heterogeneity was observed across the sequenced molecules at individual promoters, indicating the presence of epigenetically distinct cellular subpopulations.
2013-10-03 | GSE50047 | GEO