At our proposed U54 center, we will continue to conduct epigenomic analysis in cancer. While the focus of the previous award was on epigenetic processes associated with neoplastic transformation of normal cells. In this competing application, we will move a step forward to study epigenetic changes in prostate, breast, and ovarian cancer cells progressing to an aggressive phenotype, i.e., hormone-Zchemo-resistance. Based on our preliminary findings, we hypothesize that epigenetic deregulation of androgen receptor, estrogen receptor a, or TGF-B/SMAD4 signaling underlies the transition of a hormone-/chemo-sensitive to a hormone-/chemo-insensitive phenotype in cancer. Different modes of signaling-mediated transcription, including ligand-dependent and -independent functions, will be defined using integrated epigenomic data. We will develop probabilistic algorithms to predict the effect of chromosome looping and chromatin remodeling (i.e., changes of histone marks and DNA methylation) on target gene transcription, including empirical Bayesian mixture and hidden Markov modeling (for classifying spatiotemporal patterns of target genes in a signaling network), interactive modeling of transcription "hubs", stochastic modeling of permissive and non-permissive epigenetic marks, and pattern recognition algorithms for predicting transcription factor binding sites and methylation-prone or -resistant sequences. Testing and validation of these computational predictions will be performed in cancer cell lines. Assays including functional knock-in or -out of key transcription hubs will determine whether cancer cells gain or lose hormone-/chemo-sensitivity, respectively, as a result of in vitro manipulation. For translational studies, primary tumors will be used to correlate clinicopathological correlations with epigenetic changes. By taking an integrative "omics" approach, we expect to move the epigenomics field forward in at least three new directions: 1) long-range chromatin looping may be a common epigenetic mechanism of transcriptional regulation in cancer;2) histone modifications/DNA methylation of distant transcription binding sites represent previously uncharacterized biomarkers for predicting hormone-/chemo-resistance in cancer subtypes;and 3) computational modeling may support the recent notion that repressive histone modifications, rather than DNA methylation, are critical epigenetic factors in the heritable silencing of genes. Importantly, these state-of-the-art computational approaches and the vast omics data will be used for our education/outreach efforts to train young systems scientists and for collaborative studies with other researchers in the CCSB-ICBP network.
Epigenetic assays will be used to determine whether differential histone modifications and DNA methylation occur in distant transcription factor binding sites and nearby promoter regions in hormone-/chemo-insensitive cells. These analyses will be extended to a panel of cancer cell lines and primary tumors. The final objective is to identify a panel of epigenetic biomarkers for predicting responsiveness to anti-hormone treatments and chemotherapies in cancer patients.
|Teodoro, George; Kurc, Tahsin; Kong, Jun et al. (2014) Comparative Performance Analysis of Intel Xeon Phi, GPU, and CPU: A Case Study from Microscopy Image Analysis. IEEE Trans Parallel Distrib Syst 2014:1063-1072|
|Yang, Lin; Qi, Xin; Xing, Fuyong et al. (2014) Parallel content-based sub-image retrieval using hierarchical searching. Bioinformatics 30:996-1002|
|Zhang, Xinjun; Lin, Hai; Zhao, Huiying et al. (2014) Impact of human pathogenic micro-insertions and micro-deletions on post-transcriptional regulation. Hum Mol Genet 23:3024-34|
|Fang, Fang; Munck, Joanne; Tang, Jessica et al. (2014) The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res 20:6504-16|
|Hsu, Hang-Kai; Weng, Yu-I; Hsu, Pei-Yin et al. (2014) Detection of DNA methylation by MeDIP and MBDCap assays: an overview of techniques. Methods Mol Biol 1105:61-70|
|Wang, Yinu; Cardenas, Horacio; Fang, Fang et al. (2014) Epigenetic targeting of ovarian cancer stem cells. Cancer Res 74:4922-36|
|Wu, Dayong; Sunkel, Benjamin; Chen, Zhong et al. (2014) Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res 42:3607-22|
|Ghosh, Sagar; Gu, Fei; Wang, Chou-Miin et al. (2014) Genome-wide DNA methylation profiling reveals parity-associated hypermethylation of FOXA1. Breast Cancer Res Treat 147:653-9|
|Wang, Li-Shu; Burke, Carol A; Hasson, Henrietta et al. (2014) A phase Ib study of the effects of black raspberries on rectal polyps in patients with familial adenomatous polyposis. Cancer Prev Res (Phila) 7:666-74|
|Huang, Yi-Wen; Kuo, Chieh-Ti; Chen, Jo-Hsin et al. (2014) Hypermethylation of miR-203 in endometrial carcinomas. Gynecol Oncol 133:340-5|
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