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Genome-wide maps of XBP1 binding sites in different breast cancer cell lines [ChIP-Seq]

ABSTRACT: We report the application of ChIP-seq, which combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing, to map genome-wide XBP1 binding sites in different breast cancer cell lines. We showed that HIF1α motif was enriched in XBP1 binding sites in triple negative breast cancer (TNBC) cell lines, but not enriched in ER positive breast cancer cell line. We also demonstrated that different breast cancer cell lines of the same sub-type had similar XBP1 binding sites, whereas different breast cancer sub-types had majorly different XBP1 binding sites. Finally, a model was applied to integrate XBP1 ChIP-seq data with expression data to predict XBP1's direct targets in TNBC cell line; the predicted direct targets were shown to be predictive of patient survival, and the prediction power was specific to TNBC patients. The above evidence indicates that XBP1 performs important functions in TNBC by interacting with HIF1α, and such regulation mechanism is specific to TNBC, which is later proved by follow-up experiments.This study represents the first detailed anaysis of XBP1 binding sites in different breast cancer cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49952 | GEO | 2013/09/26

SECONDARY ACCESSION(S): PRJNA221365

REPOSITORIES: GEO

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Project description:Human X-box binding protein-1 (XBP1) is an alternatively spliced transcription factor that participates in the unfolded protein response (UPR), a stress signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. We have previously demonstrated that XBP1 expression is increased in antiestrogen-resistant breast cancer cell lines, and is co-expressed with estrogen receptor alpha (ER) in breast tumors. The purpose of this study is to investigate the role of XBP1 and the UPR in estrogen and antiestrogen responsiveness in breast cancer. Overexpression of spliced XBP1 (XBP1(S)) in ER-positive breast cancer cells leads to estrogen-independent growth and reduced sensitivity to growth inhibition induced by the antiestrogens Tamoxifen and Faslodex in a manner independent of functional p53. Data from gene expression microarray analyses imply that XBP1(S) acts through regulating the expression of ER, the anti-apoptotic gene BCL2, and several other genes associated with control of the cell cycle and apoptosis. Experiment Overall Design: Total RNA was isolated from six independent cultures (cell populations grown on different days from different stocks); three from MCF7/XBP1 cultures and three from the vector control cultures. MIAME 1.1 compliant data were collected as recommended by the Microarray Gene Expression Data (MGED) Society. RNA concentrations were determined by comparing the optical density ratios (260:280 nm) , and data on RNA quality was obtained using an Agilent 2100 Bioanalyzer and RNA 6000 LabChip kits (Agilent Technologies, New Castle, DE). RNA quality was assessed by visual inspection of the electropherograms from the Bioanalyzer data, and by the calculated RNA integrity numbers (RIN) and Degradometer values . Only high quality total RNA was labeled and hybridized to U133A Affymetrix GeneChips using manufacturer recommended procedures (Affymetrix, Santa Clara, CA). Standard âspiked-inâ controls also were included in each hybridization.

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Genome-wide maps of XBP1 binding sites in different breast cancer cell lines [ChIP-Seq]

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