糖皮质激素（GCs）在临床广泛应用，异常GC信号通路或GC药物副作用引发一系列代谢、免疫、心血管和精神性等疾病。GCs激活基因主要通过其受体（GR）结合到GR结合序列，而GR抑制基因的机制颇受争议。目前基因组定义增强子活性是根据启动子活性和与启动子距离来推断的，或结合其它探索性表观遗传标志，只有60%的准确率而无法据此深入研究。本课题组在前期研究中用ChIP-seqs、GRO-seqs鉴定了GR结合点、DNA结构域非依赖性GR栓系结合点及GR在转录水平调节的基因的基础上，采用ChIA-PET，根据与被抑制的启动子相互作用,和其它生物学及生物信息学方法综合定义和分类抑制性增强子，继而探索未阐明的GR抑制机制，鉴定相关的DNA结合因子，并对GR抑制作总结评估，为后续的GR抑制机制在各种疾病病理中的研究、探索特异性干预GR抑制相关疾病或副作用的药物靶点，开发新一代特异性GC药物提供新的思路。

Glucocorticoids (GCs) are widely prescribed drugs in clinic. Aberrant GC signaling pathway or the side effects of GCs can cause a series of metabolic, immune, cardiovascular and mental diseases. GCs activate their target genes by binding to GR-binding sites through their receptor (GR). However, GR repression mechanisms have been controversial. Currently, genome-wide defining the activity of enhancers is based on the activity of promoters and closeness between promoters and enhancers, or combined with other putative epigenetic markers, with 60% of accuracy, which make more detailed analysis unrelible. Our preliminary studies, using ChIP-seq and GRO-seq, have identified GR-binding regions, GR DNA-binding domain independent GR-tethering regions and GR transcriptional regulated genes. Here we propose to employ ChIA-PET, based on physical interaction with repressed promoters, combined with other biological and bioinformatic approaches to define and classify repressive GR enhancers. Novel GR repression mechanisms will be explored on the defined repressive enhancers, and related DNA-binding factors will be identified. Finally, the importance of all GR repression mechanisms will be evaluated to provide a genome-wide view of GR repression. These studies will shed new lights on understanding pathological mechanisms of GR repression in various diseases, on exploring therapeutical targets related to GR repression and on developing new generation of more specific GC drugs.