Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A RNA-seq-based gene expression profiling of radiation-induced tumorigenic mammary epithelial cells

ABSTRACT: To understand tumorigenesis and cancer progression of mammary epithelium, we established a cell model combining over-expression of human telomerase reverse transcriptase gene (hTERT) and heavy-ion radiation from normal human mammary epithelial cells. We subsequently used RNA-seq method to acquire their transcriptomes from two characteristic cell lines, an immortal epithelial cell line (I_hMEC) and a tumorigenic epithelial cell line (T_hMEC), and to look for differentially expressed genes (DEGs) between immortalization and tumorigenicity. We identified 7,053 DEGs, of which 84 were not only highly expressed but also significantly regulated. We found that house-keeping (HK) genes and tissue-specific (TS) genes were regulated differently during tumorigenesis; HK genes tend to be activated but TS genes tend to be repressed. We looked into three important pathways in cancer development: p53 signaling, cell cycle, and apoptosis. Although both immortal and tumorigenic cells have infinite potential to replicate and can escape apoptosis, a great number of genes exhibited different modulation pattern between the two processes. We also found that a significant number of DEGs were involved in epigenetic modification of chromatins. In conclusion, these findings may provide novel biomarkers in studying tumorigenicity and further our understanding of cellular mechanism(s) in the transition from immortal to tumorigenic processes. 2 samples examined: immortalized human mammary epithelial cell (I_hMEC) and tumorigenic human mammary epithelial cell (T_hMEC)

ORGANISM(S): Homo sapiens

SUBMITTER: lina ma

PROVIDER: E-GEOD-31310 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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An RNA-seq-based gene expression profiling of radiation-induced tumorigenic mammary epithelial cells.

Ma Lina L Nie Linghu L Liu Jing J Zhang Bing B Song Shuhui S Sun Min M Yang Jin J Yang Yadong Y Fang Xiangdong X Hu Songnian S Zhao Yongliang Y Yu Jun J

Genomics, proteomics & bioinformatics 20121204 6

Immortality and tumorigenicity are two distinct characteristics of cancers. Immortalization has been suggested to precede tumorigenesis. To understand the molecular mechanisms of tumorigenicity and cancer progression in mammary epithelium, we established a tumorigenic cell model by means of heavy-ion radiation of an immortal cell model, which was created by overexpressing the human telomerase reverse transcriptase (hTERT) in normal human mammary epithelial cells. We examined the expression profi ...[more]

PMID: 23317700

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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.

Dataset Information

A RNA-seq-based gene expression profiling of radiation-induced tumorigenic mammary epithelial cells

Publications

An RNA-seq-based gene expression profiling of radiation-induced tumorigenic mammary epithelial cells.

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