Chromatin Accessibility and Regulatory Network Modulation by Endocrine Disrupters

描述(由申请人提供)：我们目前对内分泌干扰物(EDCs)，如激素模拟物(异种雌激素)如何改变和维持染色质状态、基因表达模式以及改变基因组核受体结合和染色质结构模式的了解尚处于初级阶段。染色质的可及性在形成核激素受体和所有转录因子的结合格局中起着重要作用。DNaseI超敏图谱为调控DNA的全局、通用和精确描绘提供了一种强大的方法。在这项提案中，我们的目标是应用这些强大的方法来绘制与EDC相关的调控DNA环境中的变化，并定义EDC暴露对转录控制网络的影响。聚焦于异种雌激素，我们的目标是使用模型细胞系以及专门的原代细胞和原代人类组织培养系统来系统地表征暴露对调控DNA格局的影响。我们还将解决有关瞬时暴露于内皮细胞会引起持久表型效应的主要悬而未决的问题，并分析受内皮细胞干扰的转录调控网络。

DESCRIPTION (provided by applicant): Our current understanding of how endocrine-disrupting chemicals (EDCs), such as the hormone mimics ('xenoestrogens') modify and maintain chromatin states, gene expression patterns and alter genomic nuclear receptor binding and chromatin structural patterns is nascent. Chromatin accessibility plays a major role in shaping the binding landscape of nuclear hormone receptors and all transcription factors. DNaseI hypersensitivity mapping provides a powerful approach for global, generic, and precise delineation of regulatory DNA. In this proposal, we aim to apply these powerful approaches to map alterations in the regulatory DNA landscape associated with EDCs, and to define the impact of EDC exposure on transcriptional control networks. Focusing on xenoestrogens, we aim to characterize systematically the impact of exposure on the regulatory DNA landscape using model cell lines as well as specialized primary cell and primary human tissue culture systems. We will also address major outstanding questions concerning transient exposures to EDCs giving rise to lasting phenotypic effects, and analyze transcriptional regulatory networks perturbed by EDCs.