? Overall Systems Analysis of Epigenomic Architecture in Cancer Progression Despite anti-hormone therapies in patients, the cognate receptors ER? and AR can remain functional to support oncogenic signaling for advanced progression of breast and prostate cancers. Intensive studies have uncovered cellular and biochemical changes underlying the development of hormone resistance. However, epigenetic mechanisms for establishing and maintaining a hormone-resistant phenotype remain to be explored. Our preliminary studies have found remarkably similar epigenetic machineries that regulate hormone-independent gene transcription in both breast and prostate cancers. This process has multifaceted components, involving trans- and cis-acting elements, nucleosome reorganization, and chromatin interactions. To understand this complex mechanism, the San Antonio-Ohio State University Research Center for Cancer Systems Biology (SA-OSU RCCSB) has assembled a team of 21 experimental and computational investigators, and oncologists who will study a three-tiered epigenetic framework for gene regulation. First, microenvironmental cues initiate the recruitment of a specific combination of trans-bound transcription factors (TFs), called MegaTrans TFs, to ER? or AR-bound enhancers (Project 1). MegaTrans TFs are composed of diverse signaling-dependent transcription factors that activate these enhancers through receiving other signal cues without hormone stimulation. Second, this hormone-independent action requires well-orchestrated repositioning of nucleosomes, enabling maximal MegaTrans-DNA contact in target chromatin regions (Project 2). Pioneer factor FOXA1 and chromatin remodelers are also critical regulators of repositioned nucleosomes during the transition of a hormone-sensitive to -resistant phenotype. Third, this concerted action triggers chromatin movement, remotely bringing the MegaTrans/enhancer complexes in close proximity to target promoters (Project 3). Intra- and inter-chromatin interactions facilitate the formation of transcriptional architectures that efficiently and autonomously regulate ER?/AR-mediated gene expression even in the absence of agonists or in the presence of antagonists. Experimental investigators will use omics-seq platforms to map combinatorial MegaTrans complexes, repositioned nucleosomes, and topologically associated domains (TADs) that spatiotemporally regulate hormone-independent transcription. Computational scientists will then use omics data to derive 3D models of DNA-eRNA-protein interacting units in subnuclear compartments of cancer cells. Back to the bench, experimental scientists will use in silico findings to validate enhancer/gene markers that predict a hormone-resistant phenotype in patient-derived xenografts (PDXs) and clinical samples. To ensure seamless data integration of the three proposed projects, a Data Analysis and Management Core will implement customized toolkits to manage computational infrastructure and store omics-seq metadata for heuristic queries by community systems biologists. An Outreach Core will facilitate training of new-generation systems biologists and enhance collaborative efforts within the NCI's consortium and in the 4D nucleome community. An Administrative Core will provide governance and oversee rigorous evaluations of Intra-center Pilot Projects (IPPs), ensure cross-pollination between bench and in silico scientists in the SA-OSU RCCSB, and reinforce national guidelines of data sharing.
? Overall Endocrine therapies are commonly used to treat hormone-related cancers such as breast and prostate cancers. However, resistance to these anti-hormone therapies is a persistent challenge in patients. Our proposed U54 center will focus on a unique epigenetic mechanism that is exploited by hormone-resistant cancer cells to gain their growth and invasion advantages. This systems study is expected to gain molecular insight into hormone- independent gene transcription and to identify potential therapeutic targets that mitigate the development of hormone-resistant cancers.
|Li, Tianbao; Liu, Qi; Garza, Nick et al. (2018) Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing. Genome Med 10:30|
|Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro E et al. (2018) Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ER?-GREB1 Transcriptional Axis. Cancer Res 78:671-684|
|Horning, Aaron M; Wang, Yao; Lin, Che-Kuang et al. (2018) Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle-Related Transcription and Attenuated Androgen Response. Cancer Res 78:853-864|
|Chen, Zhong; Wu, Dayong; Thomas-Ahner, Jennifer M et al. (2018) Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci U S A 115:6810-6815|
|Su, Jianzhong; Huang, Yung-Hsin; Cui, Xiaodong et al. (2018) Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome Biol 19:108|
|Zhu, Xinjie; Zhang, Qiang; Ho, Eric Dun et al. (2017) START: a system for flexible analysis of hundreds of genomic signal tracks in few lines of SQL-like queries. BMC Genomics 18:749|
|Gao, Zhen; Ruan, Jianhua (2017) Computational modeling of in vivo and in vitro protein-DNA interactions by multiple instance learning. Bioinformatics 33:2097-2105|
|Tang, Binhua; Cheng, Xiaolong; Xi, Yunlong et al. (2017) Advances in Genomic Profiling and Analysis of 3D Chromatin Structure and Interaction. Genes (Basel) 8:|
|Lin, Xueqiu; Su, Jianzhong; Chen, Kaifu et al. (2017) Sparse conserved under-methylated CpGs are associated with high-order chromatin structure. Genome Biol 18:163|
|Jadhav, Rohit R; Santucci-Pereira, Julia; Wang, Yao V et al. (2017) DNA Methylation Targets Influenced by Bisphenol A and/or Genistein Are Associated with Survival Outcomes in Breast Cancer Patients. Genes (Basel) 8:|
Showing the most recent 10 out of 17 publications