Novel Comparative Pattern Count Analysis Reveals a Chronic Ethanol Induced Dynamic Shift In NF-¿B Genome-wide Promoter Binding During Liver Regeneration

We analyzed the effect of chronic alcohol intake on the genome-wide binding activity of NF-¿B during the initial response phase following partial hepatectomy. We analyzed the data in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found several ethanol-specific NF-¿B binding target promoters in the chronic adapted state.. Partial hepatectomy induced a diet-independent shift in NF-¿B binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns between ethanol and isocaloric pair-fed control groups. We found that NF-¿B bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. We, integrated the ChIP-chip results with a time series gene expression data set to identify the NF-¿B promoter binding targets that showed differential gene expression changes at the baseline-adapted condition as well as after PHx. We identified a set of differential patterns of NF-¿B binding that were specific to the ethanol and pair-fed control groups. We found the regulatory pathways and co-incident transcription factor binding motifs corresponding some of the key comparative-binding patterns.本研究分析了慢性酒精摄入对部分肝切除术（partial hepatectomy, PHx）后初始应答阶段核因子κB（NF-κB）全基因组结合活性的影响。本研究采用染色质免疫共沉淀-启动子微阵列（chromatin immunoprecipitation followed by promoter microarray, ChIP-chip）技术，分别对慢性适应状态及部分肝切除术应答状态下的样本数据进行了分析。本研究在慢性适应状态下鉴定出数个乙醇特异性的核因子κB结合靶启动子。部分肝切除术可诱导核因子κB结合位点相对于转录起始位点出现不依赖于饮食的偏移。本研究采用一种新型模式计数分析法，对乙醇喂养组与等热量配对喂养对照组中对应于时序结合模式的启动子数量进行了全面枚举与比较。本研究发现，部分肝切除术后即刻，核因子κB结合基因可介导细胞生长的负向调控与炎症应答过程。本研究将ChIP-chip结果与时序基因表达数据集进行整合，以筛选出在基线适应状态及部分肝切除术后均呈现差异基因表达变化的核因子κB启动子结合靶标。本研究鉴定出一组乙醇喂养组与配对喂养对照组所特有的核因子κB结合差异模式。本研究还发现了与部分关键比较结合模式相对应的调控通路及共现转录因子结合基序。