Omics analysis of three-dimensional transcriptional regulation

 描述(申请人提供)：在这份R01提案中，我们计划使用整合基因组学(Omics)分析来测试两个中心假设：1)TF模块形成不同的转录染色质中心并共同调节动态相互作用；2)环境或细胞刺激，如激素，触发不同的转录调节器，以促进染色质构象的动态变化。最终目标是从一维(1D)到三维(3D)尺度对TF模块进行建模和分析，并描述染色质组织和TF模块之间的关系。使用乳腺癌ERA的模型系统，我们的研究将检测1)E2介导的动态TF转录模块和染色质相互作用；以及2)这些枢纽和相互作用区域在三苯氧胺耐药的乳腺癌细胞中发生改变。我们所提出的研究的成功完成将对基因组学界和生物学家具有普遍的价值，这可能会导致更好地理解3D转录调控的原理和E2/ERA在内分泌耐药乳腺癌中的调控作用。

 DESCRIPTION (provided by applicant): In this R01 proposal, we plan to use an integrative genomics (Omics) analysis to test two central hypotheses: 1) TF modules form different transcriptional chromatin hubs and co-regulate dynamical interactomes; and 2) an environmental or cellular stimulus such as hormones triggers different transcription modulators to facilitate dynamical chromatin conformation changes. The ultimate goal is to model and analyze TF modules from one- dimension (1D) to three-dimension (3D) scale and describe the relationship between chromatin organization and TF modules. Using a model system of ERa in breast cancer, our studies will examine 1) E2-mediated dynamic TF transcription modules and chromatin interactions; and 2) these hubs and interacting domains are altered in tamoxifen resistant breast cancer cells. The successful completion of our proposed studies will be of value to the genomics community and biologists in general, which may result in the better understanding of the principle of 3D transcriptional regulation and the regulatory role of E2/ERa in endocrine resistant breast cancer.