SYSTEMS ANALYSIS OF EPIGENOMIC ARCHITECTURE IN CANCER PROGRESSION

OverallSystems Analysis of Epigenomic Architecture in Cancer ProgressionDespite anti-hormone therapies in patients, the cognate receptors ER? and AR can remain functional tosupport oncogenic signaling for advanced progression of breast and prostate cancers. Intensive studies haveuncovered cellular and biochemical changes underlying the development of hormone resistance. However,epigenetic mechanisms for establishing and maintaining a hormone-resistant phenotype remain to beexplored. Our preliminary studies have found remarkably similar epigenetic machineries that regulatehormone-independent gene transcription in both breast and prostate cancers. This process has multifacetedcomponents, 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 CancerSystems Biology (SA-OSU RCCSB) has assembled a team of 21 experimental and computationalinvestigators, 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 ofdiverse signaling-dependent transcription factors that activate these enhancers through receiving other signalcues without hormone stimulation. Second, this hormone-independent action requires well-orchestratedrepositioning of nucleosomes, enabling maximal MegaTrans-DNA contact in target chromatin regions (Project2). Pioneer factor FOXA1 and chromatin remodelers are also critical regulators of repositioned nucleosomesduring the transition of a hormone-sensitive to -resistant phenotype. Third, this concerted action triggerschromatin movement, remotely bringing the MegaTrans/enhancer complexes in close proximity to targetpromoters (Project 3). Intra- and inter-chromatin interactions facilitate the formation of transcriptionalarchitectures that efficiently and autonomously regulate ER?/AR-mediated gene expression even in theabsence of agonists or in the presence of antagonists. Experimental investigators will use omics-seq platformsto map combinatorial MegaTrans complexes, repositioned nucleosomes, and topologically associated domains(TADs) that spatiotemporally regulate hormone-independent transcription. Computational scientists will thenuse omics data to derive 3D models of DNA-eRNA-protein interacting units in subnuclear compartments ofcancer cells. Back to the bench, experimental scientists will use in silico findings to validate enhancer/genemarkers 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 Corewill implement customized toolkits to manage computational infrastructure and store omics-seq metadata forheuristic queries by community systems biologists. An Outreach Core will facilitate training of new-generationsystems biologists and enhance collaborative efforts within the NCI's consortium and in the 4D nucleomecommunity. An Administrative Core will provide governance and oversee rigorous evaluations of Intra-centerPilot Projects (IPPs), ensure cross-pollination between bench and in silico scientists in the SA-OSU RCCSB,and reinforce national guidelines of data sharing.