Reconstructing gene regulatory networks of tumorigenesis [ChIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72532 | GEO | 2016/05/13
SECONDARY ACCESSION(S): PRJNA294767
REPOSITORIES: GEO
Similar Datasets
Project description:The mechanistic links between transcription factors and the epigenetic landscape, which coordinate the deregulation of gene networks during cell transformation are largely unknown. We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. By combining transcriptome and epigenome data for each step during transformation and by integrating transcription factor (TF) - target gene associations, we identified 142 TFs and 24 chromatin remodelers/modifiers (CRMs), which are preferentially associated with specific co-expression paths that originate from deregulated gene programming during tumorigenesis. These TFs are involved in the regulation of divers processes, including cell differentiation, immune response and establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes, which are not only co-regulated but also functionally related. Further decortication of TF targets enabled us to define potential key regulators of cell transformation, which are engaged in RNA metabolism and chromatin remodelling. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of gene regulatory networks that are altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system. Examination of 4 different histone modifications marks and RNA PolII in all 3 cell lines of stepwise tumorigenesis model with biological replicates
2016-05-13 | E-GEOD-72532 | biostudies-arrayexpress
Project description:The mechanistic links between transcription factors and the epigenetic landscape, which coordinate the deregulation of gene networks during cell transformation are largely unknown. We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. By combining transcriptome and epigenome data for each step during transformation and by integrating transcription factor (TF) - target gene associations, we identified 142 TFs and 24 chromatin remodelers/modifiers (CRMs), which are preferentially associated with specific co-expression paths that originate from deregulated gene programming during tumorigenesis. These TFs are involved in the regulation of divers processes, including cell differentiation, immune response and establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes, which are not only co-regulated but also functionally related. Further decortication of TF targets enabled us to define potential key regulators of cell transformation, which are engaged in RNA metabolism and chromatin remodelling. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of gene regulatory networks that are altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system. Affymetrix SNP arrays (250K) were performed according to the manufacturer's directions on DNA extracted from BJ, BJEL and BJELM cells
2016-05-13 | E-GEOD-72531 | biostudies-arrayexpress
Project description:The mechanistic links between transcription factors and the epigenetic landscape, which coordinate the deregulation of gene networks during cell transformation are largely unknown. We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. By combining transcriptome and epigenome data for each step during transformation and by integrating transcription factor (TF) - target gene associations, we identified 142 Tfs and 24 chromatin remodelers/modifiers (CRMs), which are preferentially associated with specific co-expression paths that originate from deregulated gene programming during tumorigenesis. These Tfs are involved in the regulation of divers processes, including cell differentiation, immune response and establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes, which are not only co-regulated but also functionally related. Further decortication of TF targets enabled us to define potential key regulators of cell transformation, which are engaged in RNA metabolism and chromatin remodelling. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of gene regulatory networks that are altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system. Transcriptional activity in BJEL and BJELM cells has been evaluated and compared with that found in BJ cells; 2 biological replicates per cell line
2016-05-13 | E-GEOD-72530 | biostudies-arrayexpress
Project description:The mechanistic links between transcription factors and the epigenetic landscape, which coordinate the deregulation of gene networks during cell transformation are largely unknown. We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. By combining transcriptome and epigenome data for each step during transformation and by integrating transcription factor (TF) - target gene associations, we identified 142 TFs and 24 chromatin remodelers/modifiers (CRMs), which are preferentially associated with specific co-expression paths that originate from deregulated gene programming during tumorigenesis. These TFs are involved in the regulation of divers processes, including cell differentiation, immune response and establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes, which are not only co-regulated but also functionally related. Further decortication of TF targets enabled us to define potential key regulators of cell transformation, which are engaged in RNA metabolism and chromatin remodelling. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of gene regulatory networks that are altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system.
2016-05-13 | GSE72531 | GEO
Project description:The mechanistic links between transcription factors and the epigenetic landscape, which coordinate the deregulation of gene networks during cell transformation are largely unknown. We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. By combining transcriptome and epigenome data for each step during transformation and by integrating transcription factor (TF) - target gene associations, we identified 142 Tfs and 24 chromatin remodelers/modifiers (CRMs), which are preferentially associated with specific co-expression paths that originate from deregulated gene programming during tumorigenesis. These Tfs are involved in the regulation of divers processes, including cell differentiation, immune response and establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes, which are not only co-regulated but also functionally related. Further decortication of TF targets enabled us to define potential key regulators of cell transformation, which are engaged in RNA metabolism and chromatin remodelling. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of gene regulatory networks that are altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system.
2016-05-13 | GSE72530 | GEO
Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. We sought to compare the differences in gene expression in vHMEC when compared to isogenic HMEC cells. Two time points in the vHMEC growth phase were used to assess if continual passage of vHMEC contributed to expression differences. RNA was extracted from a total of 4 HMEC (and matched vHMEC) lines.
2015-05-09 | E-GEOD-58879 | biostudies-arrayexpress
Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. We sought to study the chromatin modification profile of human mammary epithelial cells (HMEC) and a matched isogenic variant population (vHMEC) utilising ChIP-seq. ChIP was performed against H3K27ac, H3K36me3 and H3K27me3 for a HMEC and vHMEC timpoint in one donor. H3K4me3 CHIP was performed in two donors, which were treated as biological replicates.
2015-05-09 | E-GEOD-58881 | biostudies-arrayexpress
Project description:To characterize a series of mouse colon cells that have become spontaneously transformed over time in order to identify the chromosomal and genomic alterations that take place during the development of tumorigenesis. Colorectal cancer is the third common malignancy in the United States. The stepwise progression from adenoma to carcinoma is accompanied by specific genomic alterations. Existing mouse models of human colon cancer have been induced by chemicals, viruses, or through genetic manipulation. Presented here is a unique mouse model of spontaneous transformation designed to identify the sequential steps of tumorigenesis. Normal epithelial colon cells were selectively isolated from the large intestine from eight different isogenic five-six week old C57BL/6 mice. Primary colon cells were grown in vitro with reduced serum concentration. The cells were sequentially recovered from culture based on distinct morphological changes: first, when the cells were in the pre-immortal stage and established as adherent cultures; second, as the cells bypassed crisis, increased their mitotic activity and became immortal; third, at early transformation, as the cells first formed foci; fourth, mid-transformed where the cells had higher proliferation rates in later passages; and finally, late transformed with rapid proliferation, contact inhibition, and multiple foci. The cells within each stage were analyzed using the molecular cytogenetic techniques of spectral karyotyping (SKY) and array comparative genomic hybridization (aCGH), and gene expression profiling. The late transformed cells were injected into nude mice to assess their tumorigenic potential. Spectral karyotyping revealed many recurrent structural and numerical aberrations, specifically in the late transformed cells. Loss of chromosome 4 is a consistent chromosomal aberration observed in all stages of the transformed colon cells, as well as in other tissues during the process of spontaneous transformation. Array CGH identified a pattern of gains and losses, and showed deletions of APC and Trp53 as well as a gain of Kras similar that observed in human colorectal cancer. Gene expression profiling identified the deregulation of several genes known to be involved in the progression of human colon cancer. Tumors resulted from three of the eight late transformed cultures confirming tumorigenic potential. Ultimately, the molecular characterization of spontaneously transformed murine epithelial colon cells indeed recapitulated the step wise progression of human colon cancer, and will prove to be an invaluable system in which to test potential rational intervention strategies. Mouse colon epithelial cells were isolated from the colon of 8 isogenic C57BL\6 mice. These cells were grown in reduced serum and over time spontaneously became immortal and transformed. Our objective is to compare these changes to those that occur during human colon cancer development.
2016-07-03 | E-GEOD-70790 | biostudies-arrayexpress
Project description:To characterize a series of mouse colon cells that have become spontaneously transformed over time in order to identify the chromosomal and genomic alterations that take place during the development of tumorigenesis. Colorectal cancer is the third common malignancy in the United States. The stepwise progression from adenoma to carcinoma is accompanied by specific genomic alterations. Existing mouse models of human colon cancer have been induced by chemicals, viruses, or through genetic manipulation. Presented here is a unique mouse model of spontaneous transformation designed to identify the sequential steps of tumorigenesis. Normal epithelial colon cells were selectively isolated from the large intestine from eight different isogenic five-six week old C57BL/6 mice. Primary colon cells were grown in vitro with reduced serum concentration. The cells were sequentially recovered from culture based on distinct morphological changes: first, when the cells were in the pre-immortal stage and established as adherent cultures; second, as the cells bypassed crisis, increased their mitotic activity and became immortal; third, at early transformation, as the cells first formed foci; fourth, mid-transformed where the cells had higher proliferation rates in later passages; and finally, late transformed with rapid proliferation, contact inhibition, and multiple foci. The cells within each stage were analyzed using the molecular cytogenetic techniques of spectral karyotyping (SKY) and array comparative genomic hybridization (aCGH), and gene expression profiling. The late transformed cells were injected into nude mice to assess their tumorigenic potential. Spectral karyotyping revealed many recurrent structural and numerical aberrations, specifically in the late transformed cells. Loss of chromosome 4 is a consistent chromosomal aberration observed in all stages of the transformed colon cells, as well as in other tissues during the process of spontaneous transformation. Array CGH identified a pattern of gains and losses, and showed deletions of APC and Trp53 as well as a gain of Kras similar that observed in human colorectal cancer. Gene expression profiling identified the deregulation of several genes known to be involved in the progression of human colon cancer. Tumors resulted from three of the eight late transformed cultures confirming tumorigenic potential. Ultimately, the molecular characterization of spontaneously transformed murine epithelial colon cells indeed recapitulated the step wise progression of human colon cancer, and will prove to be an invaluable system in which to test potential rational intervention strategies. Mouse colon epithelial cells were isolated from the colon of 8 isogenic C57BL\6 mice. These cells were grown in reduced serum and over time spontaneously became immortal and transformed. Our objective is to compare these changes to those that occur during human colon cancer development.
2016-07-03 | E-GEOD-72347 | biostudies-arrayexpress
Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. H3K27me3 ChIP-chip was performed on HMEC and vHMEC from 4 donors, H3K9ac was performed on cells from 2 donors. Both H3K27me3 and H3K9ac ChIP was performed on two time points for vHMEC and used the same input materia.
2015-05-09 | E-GEOD-58880 | biostudies-arrayexpress